Search

Immunotherapy based on PD-1/PD-L1 antagonists has been demonstrated to be efficacious in inducing tumor remission in patients with triple-negative breast cancer (TNBC). However, tumor immune evasion caused by the PD-1/PD-L1 pathway inhibits the immunotherapeutic effect of PD-1/PD-L1 inhibitors against TNBC. Therefore, identifying potential targets for blocking the PD-1/PD-L1 pathway is a compelling strategy for TNBC treatment. Here, we discovered that VGLL4 could inhibit PD-L1 transcription by suppressing STAT3 activation, thereby enhancing the efficacy of anti-PD-1 antibody immunotherapy in TNBC. Low expression of USP15, a deubiquitinating enzyme of VGLL4, was associated with reduced CD8 + T cell infiltration and poor prognosis in TNBC patients. USP15 was found to inhibit PD-L1 transcription, leading to increased CD8 + T cell infiltration and thus enhancing the efficacy of TNBC immunotherapy. Furthermore, SART3 regulated VGLL4 stability and PD-L1 transcription by influencing the nuclear translocation of USP15. In conclusion, our study provides new insights into the biological regulation of PD-L1, identifies a previously unrecognized regulator of this critical immune checkpoint, and highlights potential therapeutic targets for overcoming immune evasion in TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We aimed to determine whether pretreatment squamous cell carcinoma antigen (SCC-Ag) levels and the average logarithmic change in SCC-Ag levels ( Δ log SCC-Ag Δ time ) after concurrent chemoradiotherapy (CCRT) could predict treatment outcomes in patients with stage IIIC1 cervical squamous cell carcinoma (SCC). We analyzed 168 patients with stage IIIC1 cervical SCC who underwent primary CCRT and collected data on age, local extension, treatment details, hematological parameters, and tumor markers such as SCC-Ag and carcinoembryonic antigen 21-1 (Cyfra). Predictive performances of pretreatment SCC-Ag levels and Δ log SCC-Ag Δ time were assessed using receiver operating characteristic curves. Survival analysis was performed using the Cox regression model and Kaplan-Meier plots. The combination of pretreatment SCC-Ag levels and Δ log SCC-Ag Δ time showed higher area under the curve values than pretreatment SCC-Ag levels alone (area under the curve; 95% confidence interval [CI] 0.708 [0.581-0.836] vs. 0.666 [0.528-0.804], respectively). Pretreatment SCC-Ag (≥ 5 ng/ml and Cyfra levels (≥ 3.15 ng/ml) and Δ log SCC-Ag Δ time (≥ - 1.575) were significant predictors of disease-specific survival. The 5-year disease-specific survival rates significantly differed among the low-, intermediate-, and high-risk groups. Risk stratification using both pretreatment SCC-Ag levels and Δ log SCC-Ag Δ time may predict treatment outcomes of patients with stage IIIC1 SCC., (© 2024. The Author(s).)

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.

Pancreatic and colorectal cancers are often KRAS mutated and are incurable when tumor DNA or protein persists or recurs after curative intent therapy. Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). We treated 25 patients (20 pancreatic and five colorectal) who were positive for minimal residual mKRAS disease (ctDNA and/or serum tumor antigen) after locoregional treatment in a phase 1 study of fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909; study enrollment is complete with patient follow-up ongoing. Primary endpoints included safety and recommended phase 2 dose (RP2D). The secondary endpoint was tumor biomarker response (longitudinal ctDNA or tumor antigen), with exploratory endpoints including immunogenicity and relapse-free survival (RFS). No dose-limiting toxicities were observed, and the RP2D was 10.0 mg of Amph-CpG-7909. Direct ex vivo mKRAS-specific T cell responses were observed in 21 of 25 patients (84%; 59% both CD4 + and CD8 + ); tumor biomarker responses were observed in 21 of 25 patients (84%); biomarker clearance was observed in six of 25 patients (24%; three pancreatic and three colorectal); and the median RFS was 16.33 months. Efficacy correlated with T cell responses above or below the median fold increase over baseline (12.75-fold): median tumor biomarker reduction was -76.0% versus -10.2% (P < 0.0014), and the median RFS was not reached versus 4.01 months (hazard ratio = 0.14; P = 0.0167). ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors. ClinicalTrials.gov identifier: NCT04853017 ., (© 2024. The Author(s).)

A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM., Methods: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction., Results: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 -7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis., Conclusions: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis., Competing Interests: Disclosures R.M. Weinshilboum is a cofounder of and stockholder in OneOme, LLC. The other authors report no conflicts.

Background: Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF)., Objectives: This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers., Methods: Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database., Results: TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients., Conclusions: Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF., Competing Interests: Funding Support and Author Disclosures The KaRen study was supported by grants from the Fédération Française de Cardiologie/Société Française de Cardiologi and Medtronic Bakken Research Center. The PROMIS-HFpEF and SATELLITE studies were funded by AstraZeneca. Drs Michaëlsson, Gabrielsen, and Garkaviy are employees of and Dr Gan is a former employee of and hold shares in AstraZeneca, which is developing AZD4831 for the treatment of HFpEF. Dr Lund has received research grants from AstraZeneca, Novartis, Boehringer Ingelheim, Vifor-Fresenius, and Boston Scientific; has received consulting or speaker fees from AstraZeneca, Novartis, Boehringer Ingelheim, Vifor-Fresenius, Bayer, Sanofi, Merck, Myokardia, Orion Pharma, MedScape, Radcliffe Cardiology, Lexicon, and Respicardia, and has stock ownership in AnaCardio, outside the submitted work. Dr Hage has received consulting fees from Novartis, Roche Diagnostics, and AnaCardio; and has received speaker fees from Novartis and Merck Sharp & Dohme. Dr Shah has received research grant funding and consultant fees from AstraZeneca. The employer of Dr Voors (Univeristy of Groningen) received consultancy fees from Anacardio, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cytokinetics, Merck, Novartis, NovoNordisk, Eli Lilly, Moderna, Roche Diagnostics; and has received research support from NovoNordisk and Roche Diagnostics. Dr Saraste has received speaker or consulting fees from Abbot, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Pfizer. Dr Grove has received speaker or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Merck Sharp & Dohme, Lundbeck Pharma, and Organon; is an investigator in clinical studies sponsored by AstraZeneca or Bayer; and has received unrestricted research grants from Boehringer Ingelheim. Dr Richards has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Sphingotec, and Medtronic; has served as consultant to Roche Diagnostics and on the Advisory Board/ Steering Committee/Executive Committee for Roche Diagnostics, Critical Diagnostics, Pfizer, and Novartis. Dr Svedlund has received research grant funding from AstraZeneca. Dr Lam has received research support from NovoNordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a co-founder and nonexecutive director of Us2.ai. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer treatment. However, only a few patients respond to ICI treatment. Thus, uncovering clinically accessible ICI biomarkers would help identify which patients will respond well to ICI treatment. A comprehensive objective response rate (ORR) data of anti-PD-1/PD-L1 monotherapy in pan-cancer would offer the original data to explore the new biomarkers for ICIs., Methods: We systematically searched PubMed, Cochrane, and Embase for clinical trials on July 1, 2021, limited to the years 2017-2021, from which we obtained studies centering around anti-PD-1/PD-L1 monotherapy. Finally, 121 out of 3099 publications and 143 ORR data were included. All of the 31 tumor types/subtypes can be found in the TCGA database. The gene expression profiles and mutation data were downloaded from TCGA. A comprehensive genome-wide screening of ORR highly correlated mutations among 31 cancers was conducted by Pearson correlation analysis based on the TCGA database., Results: According to the ORR, we classified 31 types of cancer into high, medium, and low response types. Further analysis uncovered that "high response" cancers had more T cell infiltration, more neoantigens, and less M2 macrophage infiltration. A panel of 28 biomarkers reviewed from recent articles were investigated with ORR. We also found the TMB as a traditional biomarker had a high correlation coefficient with ORR in pan-cancer, however, the correlation between ITH and ORR was low across pan-cancer. Moreover, we primarily identified 1044 ORR highly correlated mutations through a comprehensive screening of TCGA data, among which USH2A, ZFHX4 and PLCO mutations were found to be highly correlated to strengthened tumor immunogenicity and inflamed antitumor immunity, as well as improved outcomes for ICIs treatment among multiple immunotherapy cohorts., Conclusion: Our study provides comprehensive data on ORR of anti-PD-1/PD-L1 monotherapy across 31 tumor types/subtypes and an essential reference of ORR to explore new biomarkers. We also screened out a list of 1044 immune response related genes and we showed that USH2A, ZFHX4 and PLCO mutations may act as good biomarkers for predicting patient response to anti-PD-1/PD-L1 ICIs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Opinion Statement: The development of immunotherapies for nonmelanoma skin cancer (NMSC) has lagged far behind that for melanoma in the past few decades, given that the majority of cases are surgically curable. Nevertheless, given the steady growth in the incidence rate of NMSC and attendant increase in patients with unresectable or advanced-stage tumors, the demand for systemic therapy is noticeably increasing. To date, the most widely used immunotherapeutic strategies, including immune checkpoint inhibitors and T-cell therapy, have obtained satisfactory results in some patients but not others. Even with an objective response in a fraction of patients, some accompanying adverse events may lead to intolerance and noncompliance. The expanding understanding of immune surveillance and tumor escape has provided us with novel perspectives in the field of immunotherapy. One emerging approach, the therapeutic cancer vaccine, encompasses the potential to newly "prime" T cells by activating antigen presentation in regional lymph nodes and the tumor microenvironment. Immune cells are therefore preconditioned and awakened to be ready to attack tumors. In NMSCs, multiple clinical trials of cancer vaccines are underway. The vaccine targets include tumor-associated antigens, tumor-specific antigens, oncolytic viruses, and toll-like receptors. Although clinical benefits have been shown in specific case reports and trials, various challenges remain to be resolved to guarantee applicability in the general patient population. Standing on the shoulders of pioneers expedites the pace of advances in therapeutic cancer vaccines, making them the rising star in the field of immunotherapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Hypoxia is a characteristic of many solid tumours and an adverse prognostic factor for cancer therapy. Hypoxia results in upregulation of carbonic anhydrase IX (CAIX) expression, a pH-regulating enzyme. Many human tissue studies have examined the prognostic value of CAIX expression in breast cancer but have yielded inconsistent results. Therefore, a systematic review and meta-analysis was undertaken to assess the prognostic value of CAIX expression for breast cancer patients., Methods: The electronic databases were systematically searched to identify relevant papers. The clinical outcomes included disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) in breast cancer patients. Review Manager version 5.4 was employed to analysis data from 23 eligible studies (containing 8390 patients)., Results: High CAIX expression was associated with poorer RFS [HR = 1.42, 95% CI (1.32-1.51), p < 0.00001], DFS [HR = 1.64, 95% CI (1.34-2.00), p < 0.00001], and OS [HR = 1.48, 95% CI (1.22-1.80), p < 0.0001]. Heterogeneity was observed across the studies. There was an effect of the CAIX antibody employed, scoring methods, and tumour localisation on CAIX expression., Conclusion: CAIX overexpression was significantly associated with poorer RFS, DFS, and OS in breast cancer patients. However, further work in high quantity tissue cohorts is required to define the optimal methodological approach., (© 2023. The Author(s).)

The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) protein has been indicated as an overexpressed oncoprotein in prostate cancer (PCa), associated with tumor progression and aggressiveness. Taxane-based antineoplastic drugs such as paclitaxel, docetaxel, or cabazitaxel, have been investigated in PCa treatment, namely for the development of combined therapies with the improvement of therapeutic effectiveness. This study aimed to evaluate the expression of STEAP1 in response to taxane-based drugs and assess whether the sensitivity of PCa cells to treatment with paclitaxel, docetaxel, or cabazitaxel may change when the STEAP1 gene is silenced. Thus, wild-type and STEAP1 knockdown LNCaP and C4-2B cells were exposed to paclitaxel, docetaxel or cabazitaxel, and STEAP1 expression, cell viability, and survival pathways were evaluated. The results obtained showed that STEAP1 knockdown or taxane-based drugs treatment significantly reduced the viability and survival of PCa cells. Relatively to the expression of proliferation markers and apoptosis regulators, LNCaP cells showed a reduced proliferation, whereas apoptosis was increased. However, the effect of paclitaxel, docetaxel, or cabazitaxel treatment was reversed when combined with STEAP1 knockdown. Besides, these chemotherapeutic drugs may stimulate the cell growth of PCa cells knocked down for STEAP1. In conclusion, this study demonstrated that STEAP1 expression levels might influence the response of PCa cells to chemotherapeutics drugs, indicating that the use of paclitaxel, docetaxel, or cabazitaxel may lead to harmful effects in PCa cells with decreased expression of STEAP1.

Introduction: Cancer vaccine represents a promising strategy toward personalized immunotherapy, and its therapeutic potency highly relies on the specificity of tumor antigens. Among these extensively studied tumor antigens, neoantigens, a type of short synthetic peptides derived from random somatic mutations, have been shown to be able to elicit tumor-specific antitumor immune response for tumor suppression. However, challenges remain in the efficient and safe delivery of neoantigens to antigen-presenting cells inside lymph nodes for eliciting potent and sustained antitumor immune responses. The rapid advance of biomaterials including various nanomaterials, injectable hydrogels, and macroscopic scaffolds has been found to hold great promises to facilitate the construction of efficient cancer vaccines attributing to their high loading and controllable release capacities., Areas Covered: In this review, we will summarize and discuss the recent advances in the utilization of different types of biomaterials to construct neoantigen-based cancer vaccines, followed by a simple perspective on the future development of such biomaterial-assisted cancer neoantigen vaccination and personalized immunotherapy., Expert Opinion: These latest progresses in biomaterial-assisted cancer vaccinations have shown great promises in boosting substantially potentiated tumor-specific antitumor immunity to suppress tumor growth, thus preventing tumor metastasis and recurrence.

The tumor-associated antigen mesothelin is expressed at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated. Here, we report the crystal structures of mesothelin that reveal a compact, right-handed solenoid consisting of 24 short helices and connecting loops. These helices form a nine-layered spiral coil that resembles ARM/HEAT family proteins. Glycan attachments have been identified in the structure for all three predicted N-glycosylation sites and confirmed with samples from cell culture and patient ascites. The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been reported previously. The N-terminal half of mesothelin is conformationally rigid, suitable for eliciting specific antibodies, whereas its C-terminal portion is more flexible. The structure of the C-terminal shedding-resistant fragment of mesothelin complexed with a mAb 15B6 displays an extended linear epitope and helps explain the protection afforded by the antibody for the shedding sites., Significance: The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies., Competing Interests: I. Pastan reports a patent to WO 2014031476 pending. No disclosures were reported by the other authors., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Antibody-drug conjugates (ADCs) reflect a new promising approach in prostate cancer, even more so after the practice-changing results in other malignancies, either hematologic or solid. ADCs consist of monoclonal antibodies (mAb) targeted at specific antigens overly expressed on cancer cells compared to normal cells. A cytotoxic payload is attached to the mAb using a stable linker. In prostate cancer, PSMA, STEAP1, TROP2, CD46 and B7-H3 are antigens currently being studied as targets for ADCs. In this paper, we discuss the composition of ADCs and focus on their application and challenges as treatment options in prostate cancer., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Neoantigens play a crucial role in cancer immunotherapy. However, the effectiveness and safety of neoantigen-based immunotherapies in patients with colorectal cancer (CRC), particularly in the Chinese population, have not been well studied. This study explored the feasibility and effectiveness of neoantigens in the treatment of CRC. Whole-exome sequencing (WES) and transcriptome sequencing were used to identify somatic mutations, RNA expression, and human leukocyte antigen (HLA) alleles. Neoantigen candidates were predicted, and immunogenicity was assessed. The neoantigens TSHZ3-L523P, RARA-R83H, TP53-R248W, EYA2-V333I, and NRAS-G12D from Patient 4 (PW4); TASP1-P161L, RAP1GAP-S215R, MOSPD1-V63I, and NAV2-D1973N from Patient 10 (PW10); and HAVCR2-F39V, SEC11A-R11L, SMPDL3B-T452M, LRFN3-R118Q, and ULK1-S248L from Patient 11 (HLA-A0201 + PW11) induced a heightened neoantigen-reactive T cell (NRT) response as compared with the controls in peripheral blood lymphocytes (PBLs) isolated from patients with CRC. In addition, we identified neoantigen-containing peptides SEC11A-R11L and ULK1-S248L from HLA-A0201 + PW11, which more effectively elicited specific CTL responses than the corresponding native peptides in PBLs isolated from HLA-A0201 + PW11 as well as in HLA-A2.1/K b transgenic mice. Importantly, adoptive transfer of NRTs induced by vaccination with two mutant peptides could effectively inhibit tumor growth in tumor-bearing mouse models. These data indicate that neoantigen-containing peptides with high immunogenicity represent promising candidates for peptide-mediated personalized therapy. Abbreviations: CRC: colorectal cancer; DCs: dendritic cells; ELISPOT: enzyme-linked immunosorbent spot; E:T: effector:target; HLA: human leukocyte antigen; MHC: major histocompatibility complex; Mut: mutant type; NGS: next-generation sequencing; NRTs: neoantigen-reactive T cells; PBMCs: peripheral blood mononuclear cells; STR: short tandem repeat; PBLs: peripheral blood lymphocytes; PBS: phosphate-buffered saline; PD-1: programmed cell death protein 1; TILs: tumor-infiltrating lymphocytes; RNA-seq: RNA sequencing; Tg: transgenic; TMGs: tandem minigenes; WES: whole-exome sequencing; WT: wild-type.

Purpose: Treatments for metastatic human epidermal growth factor receptor 2 (HER2)-positive tumors are improving but remain inadequate. We investigated activating antitumor immune response by combining radiation therapy with immune checkpoint inhibitors using mouse tumors overexpressing HER2, a pivotal driver oncogenic antigen, to develop new immunotherapies for metastatic HER2-positive tumors., Materials and Methods: NT2.5 cells were inoculated into the two mammary fat pads of FVB/N mice, which were divided into four groups: no treatment (Non), anti-PD-1 and anti-CTLA4 antibodies (P1C4), irradiation of the large tumor (Rad), and combination (R + P1C4) groups. Tumor growth, immunostaining of tumor-infiltrating lymphocytes, and the proportion of HER2-tumor antigen-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were analyzed., Results: In the Rad group, unirradiated and irradiated tumors shrank after treatment. Besides the directly irradiated tumors, the unirradiated tumors in the R + P1C4 group shrank the most. In the unirradiated tumors, CD8-positive T cells and FOXP3-positive T cells accumulated significantly more in the R + P1C4 group than in the P1C4 and the Rad groups (all p < 0.001). CD4-positive helper T cells accumulated significantly more in the R + P1C4 group than in the Rad group (p < 0.05), but this was not significantly different from the P1C4 group. HER2-specific CD8-positive T cells in the spleen and tumor-infiltrating lymphocytes were significantly increased in the R + P1C4 group compared to the P1C4 and Rad groups (all p < 0.0001)., Conclusion: Irradiation of HER2-positive tumors induced an antitumor immune effect against the unirradiated tumor, which was enhanced by the combined use of immune checkpoint inhibitors and was mediated by enhanced recruitment of HER2-tumor antigen-specific cytotoxic T lymphocytes at the tumor site in an HER2-positive mouse tumor model. Harnessing the distant antitumor immune response induced by the combination of radiation therapy and immune checkpoint inhibitors could be a promising treatment strategy for metastatic HER2-positive tumors., (© 2022. The Author(s).)

A study by Tcyganov et al. 1 demonstrates that peroxynitrite, an oxidant abundant in the tumor microenvironment, changes the repertoire of MHC class I peptides presented by tumors and limits immune recognition. Peroxynitrite inhibition in combination with immune checkpoint blockade enhances efficacy preclinically., Competing Interests: Declaration of interests The authors are employees of Genentech and declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Mirroring the rapid clinical performance, immune checkpoint blockade (ICB) leads a remarkable clinical advance in combating cancer, but suffers poor response in most cancers. The low presence of tumor-infiltration lymphocytes and the poor immunogenicity in tumor microenvironment (TME) are the main factors hindering the effectiveness of ICB in the treatment of immunological "cold" tumors. Aiming at boosting immune response via TME modulation, we report a near-infrared laser-guided photoimmuno-strategy in which synergistic phototherapy, immune adjuvant, and ICB are integrated into one versatile nanoporphyrin platform. The prepared nanoporphyrins are self-assembled from purpurin18-lipids and have photodynamic/photothermal and immunomodulatory effects that can be tuned under a single laser irradiation, concomitant with fluorescence or MSOT imaging. In this work, the contributions of each component in the nanoporphyrin platform were specified. In particular, phototherapy-driven in situ tumor cell death provided abundant tumor-associated antigens to initiate immune responses. With the assist of spatiotemporally delivered immune adjuvant, phototherapy potentiated tumor immunogenicity, reprogrammed "cold" tumors into "hot" ones, and sensitized tumors to ICB therapy. Further combined with PD-L1 blockade, the photoimmune-strategy substantially stimulated tumor-specific immune-responses and long-term immunological memory against primary tumor, abscopal tumor as well as metastatic foci. Such single light-primed photoimmunotherapy offers a promising solution to overcome common hurdles in ICB treatment and can potentially be integrated into existing clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We declare that this material has not been published, and is not under consideration for publication elsewhere. All authors have approved this submission., (Copyright © 2022. Published by Elsevier B.V.)

Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin β3 (β3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target β3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM., (© 2022 Wiley-VCH GmbH.)

The deeper understanding of metastasis phenomenon and detection of drug targets could be a potential approach to minimize cancer mortality. In this study, attempts were taken to unmask novel therapeutics to prevent metastasis and cancer progression. Initially, we explored the physiochemical, structural and functional insights of three metastasis tumor antigens (MTAs) and evaluated some plant-based bioactive compounds as potent MTA inhibitors. From 50 plant metabolites screened, isoflavone, gingerol, citronellal and asiatic acid showed maximum binding affinity with all three MTA proteins. The ADME analysis detected no undesirable toxicity that could reduce the drug likeness properties of top plant metabolites. Moreover, molecular dynamics studies revealed that the complexes were stable and showed minimum fluctuation at molecular level. We further performed ligand-based virtual screening to identify similar drug molecules using a large collection of 376,342 compounds from DrugBank. The results suggested that several structural analogs (e.g., tramadol, nabumetone, DGLA and hydrocortisone) may act as agonist to block the MTA proteins and inhibit cancer progression at early stage. The study could be useful to develop effective medications against cancer metastasis in future. Due to encouraging results, we highly recommend further in vitro and in vivo trials for the experimental validation of the findings., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

BACKGROUNDHead and neck squamous cell carcinoma not associated with HPV (HPV-unrelated HNSCC) is associated with a high rate of recurrence and poor survival.METHODSWe conducted a clinical trial in 14 patients with newly diagnosed HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death ligand 1 (PD-L1) and neutralizes TGF-β.RESULTSBintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses (PRs) were observed, and 12 of the 14 (86%) patients were alive and disease free at 1 year. Alterations in Treg infiltration and spatial distribution relative to proliferating CD8+ T cells indicated a reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not virus-specific responses, correlated with the development of a PR. Detection of neoepitope-specific responses and PRs in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pretreatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF-β blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multimechanism neoadjuvant immunotherapy for patients with HPV-unrelated HNSCC.CONCLUSIONOur studies provide insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant-specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced antitumor immunity following such treatment.TRIAL REGISTRATIONClinicalTrials.gov NCT04247282.FUNDINGThis work was funded by the Center for Cancer Research, the NCI, and the Intramural Research Program of the NIDCD, NIH. Bintrafusp alfa was provided by the health care business of Merck KGaA (Darmstadt, Germany), through a Cooperative Research and Development Agreement with the NCI. Additional funding was provided by ImmunityBio through a Cooperative Research and Development Agreement with the NIDCD.

Glioblastomas (GBM), the most common malignant primary adult brain tumors, are uniformly lethal and are in need of improved therapeutic modalities. GBM contain extensive regions of hypoxia and are enriched in therapy resistant brain tumor-initiating cells (BTICs). Carbonic anhydrase 9 (CA9) is a hypoxia-induced cell surface enzyme that plays an important role in maintenance of stem cell survival and therapeutic resistance. Here we demonstrate that CA9 is highly expressed in patient-derived BTICs. CA9 + GBM BTICs showed increased self-renewal and proliferative capacity. To target CA9, we developed dual antigen T cell engagers (DATEs) that were exquisitely specific for CA9-positive patient-derived clear cell Renal Cell Carcinoma (ccRCC) and GBM cells. Combined treatment of either ccRCC or GBM cells with the CA9 DATE and T cells resulted in T cell activation, increased release of pro-inflammatory cytokines and enhanced cytotoxicity in a CA9-dependent manner. Treatment of ccRCC and GBM patient-derived xenografts markedly reduced tumor burden and extended survival. These data suggest that the CA9 DATE could provide a novel therapeutic strategy for patients with solid tumors expressing CA9 to overcome treatment resistance. ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tatari, Zhang, Chafe, McKenna, Lawson, Subapanditha, Shaikh, Seyfrid, Savage, Venugopal, Moffat and Singh.)

Introduction: Neoantigens derived from tumour somatic mutations are recognised as ideal vaccine targets. Tumour neoantigens have been studied in a wide range of tumours. Most of research on neoantigens has focused just on a unique tumour and a single mutated gene. Currently, a few studies have reported using a mixture of neoantigen peptides derived from multiple genetic mutation sites in the treatment of genomic unstable advanced solid malignancies. The trial aims to evaluate the safety and efficacy of individualised tumour neoantigen peptide mixtures in the treatment of genomic unstable advanced solid malignant tumours., Methods and Analysis: This is a prospective, non-randomised, open, single-centre, single-arm, phase I trial. Patients with genomic unstable advanced solid malignancies are eligible for study participations. 20 patients will be included in the trial. Through the whole exome and transcriptome sequencing analysis of the fresh blood and tumour tissues of the enrolled patients, the 20 25-33aa antigen peptides with the highest mutation scores of the patients will be screened out, and the corresponding new antigen peptides will be synthesised and prepared. Patients will be treated with their own individualised neoantigen polypeptide combined with a polypeptide adjuvant (human granulocyte-macrophage colony-stimulating factor). The primary endpoint is safety indicators, including general and specific adverse events which will be monitored continuously. Secondary endpoints are progression-free survival, objective response rate, objective duration of remission, 1-year survival rate and overall survival., Ethics and Dissemination: This study has received approval from the Ethics Committee of Chongqing University Cancer Hospital on 21 November 2019 (207/2019). The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications., Trial Registration Number: ChiCTR1900025364., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Immunotherapy maintains the cancer-immunity cycle via re-activating the immune system, so as to achieve the purpose of anti-tumor. However, the response rate of current tumor immunotherapy strategies is still low. Even the most reported immune checkpoint block (ICB), the objective response rate (ORR) is only about 10-30%. Here, aiming at obtaining a higher response rate, we designed a cascade amplification nanocomposite consisting of the immune adjuvant polyinosinic:polycytidylic acid [Poly (I:C)] and aggregation-induced emission luminogen (AIEgen)-modified modular peptide (named PMRA). The PMRA includes: D PPA-1 peptide (P), an immune checkpoint inhibitor; PLGLAG peptide (M), a matrix metalloproteinase 2 (MMP-2) responsive sequence to promote the release of D PPA-1; RRRRRRRR peptide (R), for loading the Poly (I:C); PyTPA (A), a photosensitizer with AIE property. In cancer-immunity cycle, photodynamic therapy (PDT) mediated by PyTPA promotes the release of tumor-associated antigens (TAAs), and primes T lymphocytes. The cytokines coming from the stimulation of PDT and Poly (I:C) promote the activation of T lymphocytes. The high level of chemokines in tumor microenvironment promotes immune cells migration and infiltration in tumor with the assistance of PDT. Finally, through ICB with D PPA-1 peptide, T lymphocytes enhance the recognition of tumor cells and killing tumor cells. Immunogenic cell death induces the release of more TAAs, which will enter the next cycle and complete the full-loop again. Taking advantages of whole cancer-immunity cycle, the cascade amplification nanocomposite achieved almost 100% ORR in vivo. This concept of whole cancer-immunity cycle enhanced immunotherapy provides a novel perspective for tumor treatment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Osimertinib, a third-generation EGFR-TKI, has nowadays been applied to non-small cell lung cancer harboring activated EGFR mutation with or without T790M, but ultimately develop resistance to this drug. Here we report a novel mechanism of acquired resistance to osimertinib and the reversal of which could improve the clinical outcomes. In osimertinib-resistant lung cancer cell lines harboring T790M mutation that we established, expression of multiple EGFR family proteins and MET was markedly reduced, whereas expression of AXL, CDCP1 and SRC was augmented along with activation of AKT. Surprisingly, AXL or CDCP1 expression was induced by osimertinib in a time-dependent manner up to 3 months. Silencing of CDCP1 or AXL restored the sensitivity to osimertinib with reduced activation of SRC and AKT. Furthermore, silencing of both CDCP1 and AXL increased the sensitivity to osimertinib. Either silencing of SRC or dasatinib, a SRC family kinase (SFK) inhibitor, suppressed AKT phosphorylation and cell growth. Increased expression of AXL and CDCP1 was observed in refractory tumor samples from patients with lung cancer treated with osimertinib. Together, this study suggests that AXL/SFK/AKT and CDCP1/SFK/AKT signaling pathways play some roles in acquired osimertinib resistance of non-small cell lung cancer., (© 2022. The Author(s).)

Objectives: To study the clinical and prognostic significance of the preferentially expressed antigen of melanoma ( PRAME ) gene in the absence of specific fusion gene expression in children with B-lineage acute lymphoblastic leukemia (B-ALL)., Methods: A total of 167 children newly diagnosed with B-ALL were enrolled, among whom 70 were positive for the PRAME gene and 97 were negative. None of the children were positive for MLL - r , BCR / ABL , E2A/PBX1 , or ETV6/RUNX1 . The PRAME positive and negative groups were analyzed in terms of clinical features, prognosis, and related prognostic factors., Results: Compared with the PRAME negative group, the PRAME positive group had a significantly higher proportion of children with the liver extending >6 cm below the costal margin ( P <0.05). There was a significant reduction in the PRAME copy number after induction chemotherapy ( P <0.05). In the minimal residual disease (MRD) positive group after induction chemotherapy, the PRAME copy number was not correlated with the MRD level ( P >0.05). In the MRD negative group, there was also no correlation between them ( P >0.05). The PRAME positive group had a significantly higher 4-year event-free survival rate than the PRAME negative group (87.5%±4.6% vs 73.5%±4.6%, P <0.05), while there was no significant difference between the two groups in the 4-year overall survival rate (88.0%±4.4% vs 85.3%±3.8%, P >0.05). The Cox proportional-hazards regression model analysis showed that positive PRAME expression was a protective factor for event-free survival rate in children with B-ALL ( P <0.05)., Conclusions: Although the PRAME gene cannot be monitored as MRD, overexpression of PRAME suggests a good prognosis in B-ALL.

It is well known that glioma is currently the most malignant brain tumor. Because of the existence of blood-brain barrier (BBB) and tumor cell heterogeneity, systemic chemotherapy exerts unsatisfied therapeutic effect for the treatment of glioma after surgical resection and may even damage the body's immune system. Here, we developed an in situ sustained-release hydrogel delivery system for combined chemo-immunotherapy of glioma by combined chemotherapy drug and immunoadjuvant through the resection cavity local delivery. Briefly, glioma homing peptide modified paclitaxel targeting nanoparticles (PNP PTX ) and mannitolated immunoadjuvant CpG targeting nanoparticles (MNP CpG ) were embedded into PLGA 1750 -PEG 1500 -PLGA 1750 thermosensitive hydrogel framework (PNP PTX &MNP CpG @Gel). The in vitro and in vivo results showed that the targeting nanoparticles-hydrogel hybrid system could cross-link into a gel drug reservoir when injected into the resection cavity of glioma. And then, the sustained-release PNP PTX could target the residual infiltration glioma cells and produce tumor antigens. Meanwhile, MNP CpG targeted and activated the antigen-presenting cells, which enhanced the tumor antigen presentation ability and activated CD8 + T and NK cells to reverse immunosuppression of glioma microenvironment. This study indicated that the PNP PTX &MNP CpG @Gel system could enhance the therapeutic effect of glioma by chemo-immunotherapy., (Copyright © 2022. Published by Elsevier B.V.)

At present, there are various treatment strategies for colorectal cancer, including surgery, chemotherapy, radiotherapy, and targeted therapy. In recent years, with the continuous development of immunotherapy, immune checkpoint inhibitors (ICIs) can significantly improve the treatment of advanced colorectal cancer patients with high levels of microsatellite instability. In addition to ICIs, neoantigens, as a class of tumor-specific antigens (TSA), are regarded as new immunotherapy targets for many cancer species and are being explored for antitumor therapy. Immunotherapy strategies based on neoantigens include tumor vaccines and adoptive cell therapy (ACT). These methods aim to eliminate tumor cells by enhancing the immune response of host T-cells to neoantigens. In addition, for MSS colorectal cancer, such "cold tumors" with low mutation rates and stable microsatellites are not sensitive to ICIs, whereas neoantigens could provide a promising immunotherapeutic avenue. In this review, we summarized the current status of colorectal cancer neoantigen prediction and current clinical trials of neoantigens and discussed the difficulties and limitations of neoantigens-based therapies for the treatment of CRC., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Yue Zheng et al.)

A challenge in cancer treatment is targeting cancer cells while sparing normal cells. Thus, identifying cancer-specific neoepitopes is an active research area. Neoepitopes are generated by the accumulation of mutations; however, deadly cancer types, including pancreatic cancer, have a low mutational burden and, consequently, a paucity of neoantigens. In this issue of the JCI, Lim, Zhou, and colleagues describe a neoepitope generated upon proteolytic cleavage of the transmembrane CUB domain containing protein 1 (CDCP1). CDCP1 is overexpressed in cancer and portends a worse prognosis; previous attempts to target CDCP1 reduced cancer growth, but adversely affected the host. Here, the authors generated an antibody that specifically targeted cleaved CDCP1 (c-CDCP1) and developed a drug conjugate, a vector for radioactive ions, and a mediator of T cell activation. The therapeutics inhibited pancreatic cancer cell growth in vitro and in vivo. Exploiting proteolytic cleavage-derived neoantigens opens an attractive way for specifically targeting cancer cells.

Background: Neoantigens, new immunogenic sequences arising from tumor mutations, have been associated with response to immunotherapy and are considered potential targets for vaccination. Hepatocellular carcinoma (HCC) is a moderately mutated tumor, where the neoantigen repertoire has not been investigated. Our aim was to analyze whether tumors in HCC patients contain immunogenic neoantigens suitable for future use in therapeutic vaccination., Methods: Whole-exome sequencing and RNAseq were performed in a cohort of fourteen HCC patients submitted to surgery or liver transplant. To identify mutations, single-nucleotide variants (SNV) originating non-synonymous changes that were confirmed at the RNA level were analyzed. Immunogenicity of putative neoAgs predicted by HLA binding algorithms was confirmed by using in vitro HLA binding assays and T-cell stimulation experiments, the latter in vivo, by immunizing HLA-A*02.01/HLA-DRB1*01 (HHD-DR1) transgenic mice, and in in vitro, using human lymphocytes., Results: Sequencing led to the identification of a median of 1217 missense somatic SNV per patient, narrowed to 30 when filtering by using RNAseq data. A median of 13 and 5 peptides per patient were predicted as potential binders to HLA class I and class II molecules, respectively. Considering only HLA-A*02.01- and HLA-DRB1*01-predicted binders, 70% demonstrated HLA-binding capacity and about 50% were immunogenic when tested in HHD-DR1 mice. These peptides induced polyfunctional T cells that specifically recognized the mutated but not the wild-type sequence as well as neoantigen-expressing cells. Moreover, coimmunization experiments combining CD8 and CD4 neoantigen epitopes resulted in stronger CD8 T cell responses. Finally, responses against neoantigens were also induced in vitro using human cells., Conclusion: These results show that mutations in HCC tumors may generate immunogenic neoantigens with potential applicability for future combinatorial therapeutic strategies., Competing Interests: Competing interests: BS reports consultancy fees from Adaptimmune, Astra Zeneca, Bayer, BMS, Boston Scientific, BTG, Eisai, Eli Lilly, H3 Biomedicine, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; speaker fees from Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; research grants (to Institution) from BMS and Sirtex Medical., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cancer-associated neoantigens (neoAg) derived from tumor genomic sequencing and predictive algorithms for mutated peptides are a promising basis for therapeutic vaccines under investigation. Although these are generally designed to bind major histocompatibility complex class I and induce CD8 cytolytic T lymphocyte (CTL) activity, results from preclinical and clinical studies demonstrate that the majority of neoAg vaccines efficiently induce CD4 T helper (Th) responses but not CTL. Despite this, these vaccines have demonstrated clinical efficacy. Therefore, understanding the mechanisms of CD4 + T cell-mediated tumor protection is critical to optimizing this immunotherapeutic strategy., Methods: We investigated this phenomenon in the mineral oil-induced plasmacytoma (MOPC).315.BM (MOPC315) mouse model of multiple myeloma, a malignancy of plasma cells. MOPC315 cells express in their lambda chain a unique tumor-specific neoAg, an idiotypic (Id) peptide. We generated a vaccine formulated with this Id peptide fused to a heat shock protein HSC70 binding (HSB) motif co-delivered with poly (I:C). The immunogenicity of the Id-vaccine was measured in splenocytes by ELISpot. Mice were challenged with MOPC315 cells and antitumor immunity was assessed by co-incubating splenocytes and bone marrow mononuclear cells derived from vaccinated mice and controls, with the Id antigen and irradiated MOPC315 cells. The frequency of activated CD4 and CD8 T cells and their phenotype were characterized by flow cytometry., Results: Id-vaccine efficiently induced antigen-specific CD4 Th activity and antitumor immunity, protecting mice from MOPC315 tumor growth. CD4 cytolytic activity was not detected under these conditions. Polyfunctional CD8 T cells homed to the bone marrow microenvironment of protected mice and preferentially expanded only when restimulated ex vivo with both Id peptide and MOPC315 cells. Protective activity was abrogated by depletion of either CD4 or CD8 lymphocytes., Conclusion: These results demonstrate that Id-HSB +poly (I:C) vaccine protects against MOPC315 growth by priming Id-specific CD4 Th cells that confer protection against tumor but are not directly cytotoxic. These data indicate that activation of CD8 CTL against MOPC315-associated antigens not present in the vaccine is one of the major mechanisms of tumor immunity., Competing Interests: Competing interests: DL is an employee of Agenus and JC was an employee of Agenus at the time the research was being conducted. All other authors do not have relevant competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Integrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Notably, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinoma entities. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which has been shown to inhibit the antitumor T-cell response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this study, we investigated the effect of ITGB6 expression and antibody-mediated integrin αvβ6 inhibition on the tumor immune response in colorectal cancer., Methods: Using orthotopic and heterotopic tumor cell injection, we assessed the effect of ITGB6 on tumor growth and tumor immune response in wild type mice, mice with defective TGF-β signaling, and mice treated with anti-integrin αvβ6 antibodies. To examine the effect of ITGB6 in human colorectal cancer, we analyzed RNAseq data from the colon adenocarcinoma dataset of The Cancer Genome Atlas (TCGA-COAD)., Results: We demonstrate that expression of ITGB6 is an immune evasion strategy in colorectal cancer, causing inhibition of the antitumor immune response and resistance to immune checkpoint blockade therapy by activating latent TGF-β. Antibody-mediated inhibition of integrin αvβ6 sparked a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1) blockade therapy in ITGB6 expressing tumors, provoking a drastic increase in anti-PD-1 treatment efficacy. Further, we show that the majority of tumors in patients with colorectal cancer express sufficient ITGB6 to provoke inhibition of the cytotoxic T-cell response, indicating that most patients could benefit from integrin αvβ6 blockade therapy., Conclusions: These findings propose inhibition of integrin αvβ6 as a promising new therapy for colorectal cancer, which blocks tumor-promoting TGF-β activation, prevents tumor exclusion of cytotoxic T-cells and enhances the efficacy of immune checkpoint blockade therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Breast cancer has become the most commonly diagnosed cancer globally. The relapse and metastasis of breast cancer remain a great challenge despite advances in chemotherapy, endocrine therapy, and HER2 targeted therapy in the past decades. Innovative therapeutic strategies are still critically in need. Cancer vaccine is an attractive option as it aims to induce a durable immunologic response to eradicate tumor cells. Different types of breast cancer vaccines have been evaluated in clinical trials, but none has led to significant benefits. Despite the disappointing results at present, new promise from the latest study indicates the possibility of applying vaccines in combination with anti-HER2 monoclonal antibodies or immune checkpoint blockade. This review summarizes the principles and mechanisms underlying breast cancer vaccines, recapitulates the type and administration routes of vaccine, reviews the current results of relevant clinical trials, and addresses the potential reasons for the setbacks and future directions to explore., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu and Yu.)

Background: Harnessing the immune system to purposely recognize and destroy tumors represents a significant breakthrough in clinical oncology. Non-synonymous mutations (neoantigenic peptides) were identified as powerful cancer targets. This knowledge can be exploited for further improvements of active immunotherapies, including cancer vaccines, as T cells specific for neoantigens are not attenuated by immune tolerance mechanism and do not harm healthy tissues. The current study aimed at developing an optimized multitarget vaccine using short or long neoantigenic peptides utilizing virus-like particles (VLPs) as an efficient vaccine platform., Methods: Mutations of murine mammary carcinoma cells were identified by integrating mass spectrometry-based immunopeptidomics and whole exome sequencing. Neoantigenic peptides were synthesized and covalently linked to virus-like nanoparticles using a Cu-free click chemistry method for easy preparation of vaccines against mouse mammary carcinoma., Results: As compared with short peptides, vaccination with long peptides was superior in the generation of neoantigen-specific CD4 + and CD8 + T cells, which readily produced interferon gamma (IFN-γ) and tumor-necrosis factor α (TNF-α). The resulting anti-tumor effect was associated with favorable immune re-polarization in the tumor microenvironment through reduction of myeloid-derived suppressor cells. Vaccination with long neoantigenic peptides also decreased post-surgical tumor recurrence and metastases, and prolonged mouse survival, despite the tumor's low mutational burden., Conclusion: Integrating mass spectrometry-based immunopeptidomics and whole exome sequencing is an efficient approach for identifying neoantigenic peptides. Our multitarget VLP-based vaccine shows a promising anti-tumor effect in an aggressive murine mammary carcinoma model. Future clinical application using this strategy is readily feasible and practical, as click chemistry coupling of personalized synthetic peptides to the nanoparticles can be done at the bedside directly before injection., Competing Interests: Competing interests: MM, DES and MFB are shareholders of DeepVax GmbH, involved in the development of cancer immunotherapy., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Human carbonic anhydrase (CA) IX is a tumor-associated protein since it is scarcely present in normal tissues but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. A variety of approaches and design strategies were reported that afford CA IX/XII specific inhibitors and avoid the compromising effects of isoforms-promiscuous compounds. CA IX inhibitors hybrids/conjugates have become an important scaffold to design therapeutic agents with both CA inhibition and anti-cancer effects. In this review, we firstly present an overview of the role of CA IX in hypoxic tumors physiopathology, then provide a comprehensive update on the rational design and synthesis of small molecule CA IX inhibitors discovered since 2019. Also, their structure-activity relationship analysis studies are covered. A brief description of applications for CA IX inhibition in other therapeutic areas is also provided., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Landmark successes in oncoimmunology have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor reduction in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunologically cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells. Biomaterial-based cancer vaccines enhance the cancer-immunity cycle by harnessing cellular recruitment and activation against tumor-specific antigens. In this review, we discuss biomaterial-based vaccine strategies to induce lymphocytic responses necessary to mediate anti-tumor immunity. We focus on strategies that selectively attract dendritic cells via immunostimulatory gradients, activate them against presented tumor-specific antigens, and induce effective cross-presentation to T cells in secondary lymphoid organs, thereby generating immunity. We posit that personalized cancer vaccines are promising targets to generate long-term systemic immunity against patient- and tumor-specific antigens to ensure long-term cancer remission., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Oxytocin is an important regulator of the social brain. In some animal models of autism, notably in Magel2 tm1.1Mus -deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms, focusing on social memory performance. Using in situ hybridization (RNAscope), we have established that Magel2 and oxytocin receptor are co-expressed in the dentate gyrus and CA2/CA3 hippocampal regions involved in the circuitry underlying social memory. Then, we have shown that Magel2 tm1.1Mus -deficient mice, evaluated in a three-chamber test, present a deficit in social memory. Next, in hippocampus, we conducted neuroanatomical and functional studies using immunostaining, oxytocin-binding experiments, ex vivo electrophysiological recordings, calcium imaging and biochemical studies. We demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin receptors and of somatostatin interneurons in both DG and CA2/CA3 regions. We also revealed a delay in the GABAergic development sequence in Magel2 tm1.1Mus -deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring hippocampal alterations and social memory at adulthood. Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders., (© 2021. The Author(s).)

Cancer immunotherapy is a rapidly evolving concept that has been given the tag "fifth pillar" of cancer therapy while radiation therapy, chemotherapy, surgery and targeted therapy remain the other four pillars. This involves the stimulation of the immune system to control tumor growth and it specifically targets the neoplastic cells rather than the normal cells. Conventional chemotherapy has many limitations which include drug resistance, recurrence of cancer and severe adverse effects. Immunology has made major treatment breakthroughs for several cancers such as colorectal cancer, prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, stomach cancer, acute lymphoblastic leukaemia etc. Currently, therapeutic strategies harnessing the immune system involve Checkpoint inhibitors, Chimeric antigen receptor T cells (CAR T cells), Monoclonal antibodies, Cancer vaccines, Cytokines, Radio-immunotherapy and Oncolytic virus therapy. The molecular characterization of several tumor antigens (TA) indicates that these TA can be utilized as promising candidates in cancer immunotherapy strategies. Here in this review, we highlight and summarize the different categories of emerging cancer immunotherapies along with the immunologically recognized tumor antigens involved in the tumor microenvironment., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Our hopes of using the power of the immune system to control tumours have been partially fulfilled with anti-PD1 antibodies and other checkpoint inhibitors and the use of engineered T cells targeting lineage-specific surface markers with chimeric antigen receptors. Can these successes be generalised? Therapeutic cancer vaccines aim to educate or re-educate the immune system to recognise tumour specific or tumour associated antigens. After many false dawns, some positive data for the effectiveness of such an approach is starting to emerge in advanced solid tumours, albeit as combination therapies with checkpoint inhibitors. But is the field targeting the right antigens? Interventions using the most effective vaccine platforms to target certain sets of antigens in patients with low disease burden might bring impressive long-term benefits to patients as single agents., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology.)

The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8 + and CD4 + T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment. We conducted a phase 1 clinical trial of CHP-NY-ESO-1 with poly-ICLC in patients with advanced or recurrent esophageal cancer. CHP-NY-ESO-1/poly-ICLC (μg/mg) was administered at a dose of 200/0.5 or 200/1.0 (cohorts 1 and 2, respectively) every 2 weeks for a total of six doses. The primary endpoints were safety and immune response. The secondary endpoint was tumor response. In total, 16 patients were enrolled, and six patients in each cohort completed the trial. The most common adverse event (AE) was injection site skin reaction (86.7%). No grade 3 or higher drug-related AEs were observed. No tumor responses were observed, and three patients (30%) had stable disease. The immune response was comparable between the two cohorts, and all patients (100%) achieved antibody responses with a median of 2.5 vaccinations. Comparing CHP-NY-ESO-1 alone to the poly-ICLC combination, all patients in both groups exhibited antibody responses, but the titers were higher in the combination group. In a mouse model, adding anti-PD-1 antibody to the combination of CHP-NY-ESO-1/poly-ICLC suppressed the growth of NY-ESO-1-expressing tumors. Combining the vaccine with PD-1 blockade holds promise in human trials., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: A first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2 + patients with advanced melanoma., Methods: Patient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-γ enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins., Results: Sixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against ≥3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8 + T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis., Conclusions: Combined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents., Trial Registration Number: NCT01876212., Competing Interests: Competing interests: WJS, DM, YL, FD, LK, AB, DBL, AR, MD, JLT, MC, RJF, JNF and PK declare no competing interests. TJL was an employee of Thermo Fisher Scientific during the performance of this work. TJL, LM, EL and GML are/were employees of Thermo Fisher Scientific during the performance of this work. LHB declares the following unrelated advisory activities: StemImmune/Calidi Scientific and Medical Advisory Board, April 6, 2017–present; SapVax Advisory Board meetings November 15, 2017; December 6, 2018; NextCure, Scientific Advisory Board, 2018–2020; Western Oncolytics, Scientific Advisory Board, 2018–present; Torque Therapeutics, Scientific Advisory Board, 2018–2020; Khloris, Scientific Advisory Board, 2019–present; Pyxis, Scientific Advisory Board, 2019–present; Cytomix, Scientific Advisory Board, 2019–present; Vir, Scientific Advisory Board meeting, February 2020; DCprime, Scientific Advisory Board meeting, November 2020; RAPT, Scientific Advisory Board, 2020–present; Takeda, Scientific Advisor, 2020–present; EnaraBio scientific advisor, February 2021. AT declares the following unrelated advisory activities: Receipt of fees for consulting and/or advisory board participation from Partner Therapeutics, Merck, Bristol Myers Squibb, Novartis, Genentech-Roche, Array Biopharma, Sanofi-Genzyme/Regeneron, Pfizer, EMD Serono, NewLink Genetics, BioNTech, Immunocore, and Eisai; participation in a Data Safety Monitoring Board for Incyte; involvement with institution contracted research with Merck, OncoSec, Genentech-Roche, Bristol Myers Squibb, Amgen and Clinigen. HT declares the following unrelated consulting Honoraria: BMS, Novartis, Merck, Genentech, Eisai, Iovance, Boxer Capital, Karyopharm. Research Funding to Institution: BMS, Novartis, Merck, Genentech, GSK. JMK declares the following unrelated advisory activities and funding: Advisory Role: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Elsevier, Amgen, Checkmate Pharmaceuticals, Harbour BioMed, Istari Oncology, OncoSec, Scopus BioPharma, Pfizer; Speakers’ Bureau: Bristol Myers Squibb unbranded IO; Research Funding: Amgen, Bristol Myers Squibb, Castle Biosciences, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapeutics, Novartis, Merck., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cancer/testis antigens (CTAs) are a group of tumor antigens expressed in numerous cancer tissues, as well as in the testis and placental tissues. There are over 200 CTAs supported by serology and expression data. The expression patterns of CTAs reflect the similarities between the processes of gametogenesis and tumorigenesis. It is notable that CTAs are highly expressed in three types of cancers (lung cancer, bladder cancer, and skin cancer), all of which have a metal etiology. Here, we review the expression, regulation, and function of CTAs and their translational prospects as cancer biomarkers and treatment targets. Many CTAs are highly immunogenic, tissue-specific, and frequently expressed in cancer tissues but not under physiological conditions, rendering them promising candidates for cancer detection. Some CTAs are associated with clinical outcomes, so they may serve as prognostic biomarkers. A small number of CTAs are membrane-bound, making them ideal targets for chimeric antigen receptor (CAR) T cells. Mounting evidence suggests that CTAs induce humoral or cellular immune responses, providing cancer immunotherapeutic opportunities for T-cell receptors (TCRs), CAR T cell, antibody-based therapy and peptide- or mRNA-based vaccines. Indeed, CTAs are the dominating non-mutated targets in mRNA cancer vaccine development. Clinical trials on CTA TCR and vaccines have shown effectiveness, safety, and tolerance, but these successes are limited to a small number of patients. In-depth studies on CTA expression and function are needed to improve CTA-based immunotherapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines.

Peptide-based cancer vaccines rely upon the strong activation of the adaptive immune response to elicit its effector function. They have shown to be highly specific and safe, but have yet to prove themselves as an efficacious treatment for cancer in the clinic. This is for a variety of reasons, including tumour heterogeneity, self-tolerance, and immune suppression. Importance has been placed on the overall design of peptide-based cancer vaccines, which have evolved from simple peptide derivatives of a cancer antigen, to complex drugs; incorporating overlapping regions, conjugates, and delivery systems to target and stimulate different components of antigen presenting cells, and to bolster antigen cross-presentation. Peptide-based cancer vaccines are increasingly becoming more personalised to an individual's tumour antigen repertoire and are often combined with existing cancer treatments. This strategy ultimately aids in combating the shortcomings of a more generalised vaccine strategy and provides a comprehensive treatment, taking into consideration cancer cell variability and its ability to avoid immune interrogation., Competing Interests: SJ receives grants from CBI and Oxford Vacmedix UK Ltd, a spin-out from University of Oxford who develop recombinant overlapping peptide (ROP) cancer vaccines. NB-B consults for Oxford Vacmedix UK Ltd., (Copyright © 2021 Stephens, Burgess-Brown and Jiang.)

Neoepitopes or neoantigens are a spectrum of unique mutations presented in a particular patient's tumor. Neoepitope-based adoptive therapies have the potential of tumor eradication without undue damaging effect on normal tissues. In this context, methods based on the T cell receptor (TCR) engineering or chimeric antigen receptors (CARs) have shown great promise. This review focuses on the TCR-like CARs and TCR-CARs directed against tumor-derived epitopes, with a concerted view on neoepitopes. We also address the current limitations of the field to know how to harness the full benefits of this approach and thereby design a sustained and specific antitumor therapy.

Recurrence or de novo infection of hepatitis C virus (HCV) after liver transplantation (LT) has been associated with progressive graft hepatitis that can be improved by treatment with novel direct-acting antivirals. Cases of rejection episodes have been described during and after HCV treatment. The evolution of innate and adaptive immune response during and after cure of HCV LT is unknown. We studied 74 protein biomarkers in the plasma of LT patients receiving antiviral therapy. In addition, deep immune phenotyping of both the myeloid and lymphoid immune cell subsets in peripheral blood mononuclear cells was performed. We found that LT patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers, such as C-X-Cmotif chemokine 10 (CXCL10), caspase 8, C-C motif chemokine 20 (CCL20), CCL19, interferon γ, CUB domain-containing protein 1 (CDCP1), interleukin (IL)-18R1, CXCL11, CCL3, IL8, IL12B, tumor necrosis factor-beta, CXCL6, osteoprotegerin, IL10, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor, urokinase-type plasminogen activator, neurotrophin-3, CCL4, IL6, tumornecrosis factor receptor superfamily member 9, programmed death ligand 1, IL18, and monocyte chemotactic protein 1, and enrichment of peripheral immune cell subsets unlike patients without HCV infection who received transplants. Interestingly, patients who cleared HCV after LT did not normalize the altered inflammatory milieu nor did the peripheral immune cell subsets normalize to what would be seen in the absence of HCV recurrence. Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets after LT are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV after LT did not trigger rejection episodes in many patients., (Copyright © 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

The immunoprevention of cancer and cancer recurrence is an important area of concern for the scientific community and society as a whole. Researchers have been working for decades to develop vaccines with the potential to alleviate these health care and economic burdens. So far, vaccines have made more progress in preventing cancer than in eliminating already established cancer. In particular, vaccines targeting oncogenic viruses, such as the human papillomavirus and the hepatitis B virus, are exceptional examples of successful prevention of virus-associated cancers, such as cervical cancer and hepatocellular carcinoma. Cancer-preventive vaccines targeting nonviral antigens, such as tumor-associated antigens and neoantigens, are also being extensively tested. Here, we review the currently approved preventive cancer vaccines; discuss the challenges in this field by covering ongoing preclinical and clinical human trials in various cancers; and address various issues related to maximizing cancer vaccine benefit.

In this communication, we will analyze some important factors and immunological phenomena related to neoantigen cancer vaccines, with particular emphasis on recently published Phase I clinical trials. Several obstacles and issues are addressed that challenge the current paradigm and inquire if neoantigens, which are essentially single-use vaccine candidates, are legitimate targets to induce protective immune responses with regard to the evolving mutational landscape. We also share insights into the striking similarities between cancer and antigenically variable pathogens and suggest that any successful vaccine against either should demonstrate a similar property: efficient induction of a diverse pool of immune cells equipped to prevent immune escape. Hence, to confront antigenic variability directly, we have employed our innovative vaccine concept, Variable Epitope Libraries, composed of large combinatorial libraries of heavily mutated epitopes, as a "universal" vaccine platform. Collectively, we offer critical analyses on key issues, which ultimately reflect on the prospective clinical relevance of personalized neoantigen vaccines which is still undefined.

Although melanoma remains the deadliest skin cancer, the current treatment has not resulted in the desired outcomes. Unlike chemotherapy, immunotherapy has provided more tolerable approaches and revolutionized cancer therapy. Although dendritic cell-based vaccines have minor side effects, the undesirable response rates of traditional approaches have posed questions about their clinical translation. The immunosuppressive tumor microenvironment can be the underlying reason for their low response rates. Immune checkpoints and indoleamine 2,3-dioxygenase have been implicated in the induction of immunosuppressive tumor microenvironment. Growing evidence indicates that the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Protein kinase B (PKB) (PI3K/AKT) pathways, as the main oncogenic pathways of melanoma, can upregulate the tumoral immune checkpoints, like programmed death-ligand 1. This study briefly represents the main oncogenic pathways of melanoma and highlights the cross-talk between these oncogenic pathways with indoleamine 2,3-dioxygenase, tumoral immune checkpoints, and myeloid-derived suppressor cells. Moreover, this study sheds light on a novel tumor antigen on melanoma, which has substantial roles in tumoral immune checkpoints expression, indoleamine 2,3-dioxygenase secretion, and stimulating the oncogenic pathways. Finally, this review collects the lessons from the previous unsuccessful trials and integrates their lessons with new approaches in RNA-modified dendritic cell vaccines. Unlike traditional approaches, the advances in single-cell RNA-sequencing techniques and RNA-modified dendritic cell vaccines along with combined therapy of the immune checkpoint inhibitors, indoleamine 2,3-dioxygenase inhibitor, and RNA-modified dendritic cell-based vaccine can overcome these auto-inductive loops and pave the way for developing robust dendritic cell-based vaccines with the most favorable response rate and the least side effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shadbad, Hajiasgharzadeh, Derakhshani, Silvestris, Baghbanzadeh, Racanelli and Baradaran.)