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Most high grade serous ovarian cancers (HGSOC) originate in the fallopian tube but spread to the ovary and peritoneal cavity, highlighting the need to understand antitumor immunity across HGSOC sites. Using spatial analyses, we discover that tertiary lymphoid structures (TLSs) within ovarian tumors are less developed compared with TLSs in fallopian tube or omental tumors. We reveal transcriptional differences across a spectrum of lymphoid structures, demonstrating that immune cell activity increases when residing in more developed TLSs and produce a prognostic, spatially derived TLS signature from HGSOC tumors. We interrogate TLS-adjacent stroma and assess how normal mesenchymal stem cells MSCs (nMSCs) may support B cell function and TLS, contrary to cancer-educated MSCs (CA-MSCs) which negate the prognostic benefit of our TLS signature, suggesting that pro-tumorigenic stroma could limit TLS formation. [Display omitted] • TLS activity varies by HGSOC anatomical site • An in situ -derived TLS signature from ovarian tumors is prognostic • TLS state governs B cell immunity • Cancer reprogrammed stroma blunts B cell function and is implicated in TLS regulation Therapies that harness the immune response are lacking for ovarian cancer patients. MacFawn et al. utilize spatial transcriptomics to understand how tumor site, stroma, and cellular interactions govern the activity of tertiary lymphoid structures. These studies reveal how we may promote development of these prognostic structures to bolster adaptive antitumor immunity. [ABSTRACT FROM AUTHOR]

Suboptimal CD4+ T cell activation leads to a hyporesponsive state in mice characterized by incomplete differentiation, limited cytokine production, and changes in T helper (Th) subsets. Together, these factors impair CD4+ T cell trafficking to the tumor and enable the immune evasion of tumor cells. Sustained inflammation, antigen stimulation, and suppressive factors induce CD4+ T cell dysfunctions during tumor progression in murine models. Despite sharing some phenotypic similarities with CD8+ T cells in mouse and human, CD4+ T cell dysfunctions are distinct and should be viewed through the lens of Th subset differentiation. Since CD4+ T cells can help multiple parameters of the innate and adaptive immune response, reinvigorating CD4+ T cells holds great potential in enhancing various immunotherapies, including immune checkpoint blockade, cancer vaccines, and the use of CAR T cells. CD4+ T cells are crucial for enhancing the functions of antigen-presenting cells, increasing CD8+ T cell effector differentiation, driving B cell activation and antibody affinity maturation, and temporally sustaining immune efficacy during cancer progression. As a result, CD4+ T cells serve as a central nexus that directs the initiation and coordination of an immune response. Thus, a deeper understanding of the nature, impact, and restorability of CD4+ T cell dysfunction holds vast potential in guiding therapeutic strategies to effectively harness the potential of these cells in cancer treatments. CD4+ T cells are crucial in generating and sustaining immune responses. They orchestrate and fine-tune mammalian innate and adaptive immunity through cell-based interactions and the release of cytokines. The role of these cells in contributing to the efficacy of antitumor immunity and immunotherapy has just started to be uncovered. Yet, many aspects of the CD4+ T cell response are still unclear, including the differentiation pathways controlling such cells during cancer progression, the external signals that program them, and how the combination of these factors direct ensuing immune responses or immune-restorative therapies. In this review, we focus on recent advances in understanding CD4+ T cell regulation during cancer progression and the importance of CD4+ T cells in immunotherapies. [ABSTRACT FROM AUTHOR]

• CD36 is expressed by cancer cells and cancer-associated immune cells. • Lipid uptake by CD36 can both promote and inhibit cancer progression. • Thrombospondin-1 binding to CD36 can both promote and inhibit cancer progression. • Oxidized low-density lipoprotein binding promotes cancer progression. The membrane protein CD36 is a lipid transporter, scavenger receptor, and receptor for the antiangiogenic protein thrombospondin 1 (TSP1). CD36 is expressed by cancer cells and by many associated cells including various cancer-infiltrating immune cell types. Thereby, CD36 plays critical roles in cancer, and it has been reported to affect cancer growth, metastasis, angiogenesis, and drug resistance. However, these roles are partly contradictory, as CD36 has been both reported to promote and inhibit cancer progression. Moreover, the mechanisms are also partly contradictory, because CD36 has been shown to exert opposite cellular effects such as cell division, senescence and cell death. This review provides an overview of the diverse effects of CD36 on tumor progression, aiming to shed light on its diverse pro- and anti-cancer roles, and the implications for therapeutic targeting. [ABSTRACT FROM AUTHOR]

Siglec-15 is a highly conserved member of the Siglec family, expressed on osteoclasts, a subset of myeloid cells and some cancer cells. Except for regulating osteoclast differentiation, Siglec-15 engages in immunoregulation as an immune suppressor. Siglec-15 functions as an immunosuppressive molecule in tumor-associated macrophage-mediated T cell immunity in the tumor microenvironment (TME), which makes Siglec-15 to be an emerging and promising target for normalization cancer immunotherapy. Besides, Siglec-15 interacts with sialylated pathogens and modulates host immune response against microbial pathogens by altering cytokine production and/or phagocytosis, which further broadens the underlying pathophysiological roles of Siglec-15. The fact that N-glycosylation and sialylation of Siglec-15 play a pivotal role in Siglec-15 biological function indicates that targeting certain post-translational modification may be an effective strategy for targeting Siglec-15 therapy. In-depth exploring Siglec-15 biology function is crucial for better design of Siglec-15-based therapy according to different clinical indications. [ABSTRACT FROM AUTHOR]

TA-MSCs impair NK cell immune activity through direct and indirect mechanisms to promote tumor progression. Blocking TA-MSCs' inhibitory effects on NK cells, or combined with conventional therapies, induce tumor regression. [Display omitted] • TA-MSCs influence immune cells to foster immunosuppressive tumor microenvironment. • Tumor-infiltrating NK cells display reduced number and impaired antitumor activity. • TA-MSCs reshape NK cells with the tumor microenvironment by distinct mechanisms. • Blocking the regulatory effect of TA-MSCs on NK cells holds promise for tumor therapy. Mesenchymal stem/stromal cells (MSCs), originating from normal tissues, possess the capacity to home to tumor sites and differentiate into tumor-associated MSCs (TA-MSCs), which are instrumental in shaping an immunosuppressive milieu within tumors. Natural killer (NK) cells, integral to the innate immune system, are endowed with the ability to eradicate target cells autonomously, serving as an immediate defense against neoplastic growths. Nonetheless, within the tumor microenvironment (TME), NK cells often exhibit a decline in both their numerical presence and functionality. TA-MSCs have been shown to exert profound inhibitory effects on the functions of tumor-infiltrating immune cells, notably NK cells. Understanding the mechanisms by which TA-MSCs contribute to NK cell dysfunction is critical for the advancement of immune surveillance and the enhancement of tumoricidal responses. This review summarizes existing literature on NK cell modulation by TA-MSCs within the TME and proposes innovative strategies to augment antitumor immunity. [ABSTRACT FROM AUTHOR]

There is a strong rationale for targeting HER3, as HER3 contributes to tumorigenesis and treatment resistance. However, the prognostic role of HER3 and their association with immunoregulatory protein expression has not been established. The main objective of this study was to investigate the prognostic role of HER3 expression and identify immunoregulatory marker expression according to HER3 status. HER3 expression and 10 immunoregulatory protein (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/B7-H3/B7-H4) expression was identified in 320 stage I-III breast cancer patients who received curative surgery at Seoul National University Hospital in 2008. The median follow-up duration was 88.8 months. Criteria for HER3 IHC was adopted from HER2 IHC score and only those with 3 + was considered positive. Among 320 patients, 213 (67.2 %) had luminal A disease, 30 (9.5 %) had luminal B disease, 28 (8.8 %) had HER2-positive disease, and 46 (14.5 %) had triple negative disease. HER3 expression was shown in 153 patients (47.8 %). Tumors with HER3-expression had more immunogenic tumor microenvironment compared to HER3-negative tumor. In addition, patients with HER3 expression had favorable 5-year relapse free survival compared to HER3-negative patients (5-year RFS 92.5 % vs. 85.2 %, p = 0.038). However, in the multivariate analysis, HER3 expression was not a prognostic factor, but expression of immunoregulatory protein was a prognostic factor. This study identified immunoregulatory protein expression according to HER3 status in breast cancer patients. As tumor with HER3 expression have more immunogenic microenvironment, investigating combination treatment of HER3 targeting agent and immunotherapy in HER3 expressing breast cancer may be promising. • HER3 contributes to tumorigenesis and treatment resistance in breast cancer. • Early breast cancer with HER3-expression had immunogenic tumor microenvironment. • HER3 expression was associated with favorable 5-year relapse free survival. • Combination treatment of HER3 targeting agent and immunotherapy may be promising. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy. A controlled-release thermosensitive hydrogel containing a pH-responsive anti-CD276 scFV engineered nanovesicles with multifunctional strategies was designed to overcome chemoresistant breast cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies. Elevated tumor glycolysis and lactate production are robust suppressors of antitumor immunity in multiple cancer subtypes. Loss of mitochondrial function is a hallmark of CD8+ T cell exhaustion and might be a promising metabolic target for improving patient responses to CAR-T and/or ICB therapy, pending future investigations. IL4I1-driven tryptophan catabolism and aryl hydrocarbon receptor activation may constitute a resistance mechanism to ICB and/or IDO1 inhibitors across cancer subtypes. We propose that the metabolic profile of the TME promotes both initiation and disruption of the cancer-immunity cycle. Hence, targeting cellular metabolism in the TME may improve responsiveness to T cell-based immunotherapies. [ABSTRACT FROM AUTHOR]

Single-cell technologies are emerging as powerful tools for cancer research. These technologies characterize the molecular state of each cell within a tumor, enabling new exploration of tumor heterogeneity, microenvironment cell-type composition, and cell state transitions that affect therapeutic response, particularly in the context of immunotherapy. Analyzing clinical samples has great promise for precision medicine but is technically challenging. Successfully identifying predictors of response requires well-coordinated, multi-disciplinary teams to ensure adequate sample processing for high-quality data generation and computational analysis for data interpretation. Here, we review current approaches to sample processing and computational analysis regarding their application to translational cancer immunotherapy research. [ABSTRACT FROM AUTHOR]

• Oral cancer patients were classified into high- or low-immune infiltration group. • Both groups were evenly distributed in ENE-positive patients. • ENE-positive low immune group (ENE+/Low) followed worst clinical outcome. • Genes upregulated in ENE+/Low involve in proliferation related pathways. • Immune status in primary site may modify clinical outcomes of ENE+ oral cancer. Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown. We identified 234 human papillomavirus-negative (HPV−) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival. Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The combination of ENE positivity and low immune infiltration was strongly associated with poor overall survival (OS) compared to the combination of ENE positivity and high immune infiltration [hazard ratio 2.04 (95 %CI, 1.08–3.83); p = 0.024]. The immune infiltration status was not associated with OS rates in patients with ENE-negative or node negative tumors. Overall Immune infiltration at the primary site was significantly associated with clinical outcome of OSCC patients with ENE. [ABSTRACT FROM AUTHOR]

• Extracellular vesicles (EVs) play a cellular communication role in the tumor microenvironment. • EVs derived from immune cells are key players in regulating tumors. • EVs are involved in anti-tumor immunotherapy. • Immune cell-based EVs have been utilized in numerous oncology clinical trials. Extracellular vesicles (EVs), which have a lipid nano-sized structure, are known to contain the active components of parental cells and play a crucial role in intercellular communication. The progression and metastasis of tumors are influenced by EVs derived from immune cells, which can simultaneously stimulate and suppress immune responses. In the past few decades, there has been a considerable focus on EVs due to their potential in various areas such as the development of vaccines, delivering drugs, making engineered modifications, and serving as biomarkers for diagnosis and prognosis. This review focuses on the substance information present in EVs derived from innate and adaptive immune cells, their effects on the immune system, and their applications in cancer treatment. While there are still challenges to overcome, it is important to explore the composition of immune cells released vesicles and their potential therapeutic role in tumor therapy. The review also highlights the current limitations and future prospects in utilizing EVs for treatment purposes. [ABSTRACT FROM AUTHOR]

Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation. • Eighty-three lymph node dissections following neoadjuvant immunotherapy for stage III metastatic melanoma were assessed. • There was strong reproducibility in assessment of INMC pathological response category and percentage of viable melanoma. • High fibrosis was associated with a lack of recurrence and increased RFS, representing a possible biomarker. • Two different scoring systems of response were assessed and both scoring systems correlated with a lack of recurrence. • High fibrosis was also associated with increased levels of B cells within the tumour bed. [ABSTRACT FROM AUTHOR]

High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936). In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10−16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted. • TMB-H failed to predict improved or clinically relevant response to ICB in all cancer types. • Cancer types where TMB-H does not predict response generally show no relationship between tumor neoantigen load and CD8 T-cell infiltration. • Further studies should be carried out before application of TMB-H as a biomarker for ICB in all cancer types. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized cancer treatment in the last decade, and strategies to re-activate cytotoxic immunity are now standard of care in several malignancies. Despite rapid advances in immunotherapy for most solid cancers, progress in immunotherapy against pancreatic ductal adenocarcinoma (PDAC) has been exceptionally difficult. This is true for several approaches, most notably immune checkpoint inhibitors (ICIs) and GM-CSF cell-based vaccines (GVAX). Though many immunotherapies have been explored in clinical trials, few have shown significant therapeutic efficacy. Further, many have shown high rates of serious adverse effects and dose-limiting toxicities, and to date, immunotherapy regimens have not been successfully implemented in PDAC. Here, we provide a comprehensive summary of the key clinical trials exploring immunotherapy in PDAC, followed by a brief discussion of emerging molecular mechanisms that may explain the relative failure of immunotherapy in pancreas cancer thus far. [ABSTRACT FROM AUTHOR]

The complex tumor microenvironment is a most important factor in cancer development. The biological microenvironment is composed of a variety of barriers including the extracellular matrix and associated cells such as endothelia cells, pericytes, and cancer-associated fibroblasts. Different strategies can be utilized to enhance nanoparticle-based drug delivery and distribution into tumor tissues addressing the extracellular matrix or cellular components. In addition to the biological microenvironment, the immunological conditions around the tumor tissue can be very complicated and cancer cells have various ways of evading immune surveillance. Nanoparticle drug delivery systems can enhance cancer immunotherapy by tuning the immunological response and memory of various immune cells such as T cells, B cells, macrophages, and dendritic cells. In this review, the main components in the tumor biological and immunological environment are discussed. The focus is on recent advances in nanoparticle-based drug delivery systems towards targets within the tumor microenvironment to improve cancer chemotherapy and immunotherapy. The main components in the tumor biological and immunological environment are discussed. The focus is on recent advances in nanoparticle-based drug delivery systems towards targets within the tumor microenvironment to improve cancer chemotherapy and immunotherapy. Image 1 [ABSTRACT FROM AUTHOR]

Cancer elimination in humans can be achieved with immunotherapy that relies on T lymphocyte-mediated recognition of tumor antigens. Several types of these antigens have been recognized based on their cellular origins and expression patterns, while their detection has been greatly facilitated by recent achievements in next-generation sequencing and immunopeptidomics. Some of them have been targeted in clinical trials with various immunotherapy approaches, while many others remain untested. Here, we discuss molecular identification of different tumor antigen types, and the clinical safety and efficacy of targeting them with immunotherapy. Additionally, we suggest strategies to increase the efficacy and availability of antigen-directed immunotherapies for treatment of patients with metastatic cancer. [ABSTRACT FROM AUTHOR]

Reciprocal interactions between tumor cells and immune cells shape the tumor microenvironment. Recent studies indicate that enhanced cell cycle activity in cancer cells suppresses antitumor immunity. Herein we discuss potential mechanisms by which cell cycle programs intrinsic to tumor cells are coupled to immune behavior, with consequences for immunotherapy. [ABSTRACT FROM AUTHOR]

• Complement system proteins and their regulators promote tumor growth. • Its activation is an important prerequisite for role in tumor growth and anti-tumor response. • Its contradictory role in cancer might be a very crucial factor for the positive outcomes of immunotherapies. • Complement resistance not only influences the course of disease but also the patients' prognosis. Complement system proteins, their regulators and endpoint effector complex significantly promote tumor growth by upregulation of oncogenic growth factors, activation of mitogenic signalling pathways and breakage of normal cell cycle. Contrastingly, complement cascades, initiated by anti-tumor therapeutic antibodies, also play a pivotal role in therapy response. This contradictory role of complement system possibly be a very crucial factor for the outcomes of antibody mediated immunotherapies. Herein, we reviewed the twin role of the complement system in cancer and also the genetic variations in complement system genes. Future studies should be focused on the biomarker discovery for the personalised cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Recurrence of malignant tumor after surgical resection is the main reason of cancer treatment failure. Here, a novel kind of silk inverse opal particles (SIOPs) for post-surgical tumor treatment is presented, and it is derived from colloid crystal bead templates by negatively replicating. Because of their abundant uniform nanopores, interconnected nanochannels and excellent biocompatibility, SIOPs could not only carry great amount of anti-tumor drugs for tumor therapy, but also could provide support for cell adhesion, proliferation and differentiation as the 3D spherical scaffolds which is beneficial to the tissue repair at resection sites. It is demonstrated that the antibody drugs could maintain their high biological activity without any influences during the preparation of SIOPs and these particles were able to enhance the therapeutic efficacy and promote tissue regeneration after surgical resection with their multifunctional features. These prominent properties indicate the great potentials of SIOPs as a promising strategy for efficient postoperative cancer therapy. [ABSTRACT FROM AUTHOR]

We conducted a retrospective exploratory analysis to evaluate the effects of baseline tumour immune infiltrate on disease-free survival (DFS) outcomes in patients with fully resected stage IIC–IIIC melanoma receiving adjuvant vemurafenib monotherapy or placebo in the BRIM8 study. BRIM8 was a phase III, international, double-blind, randomised, placebo-controlled study. Eligible patients with BRAF V600 mutation–positive, completely resected melanoma were randomly assigned to oral vemurafenib (960 mg twice daily) or matching placebo for 52 weeks. The primary end point was DFS. The association of CD8+ T-cell infiltration and programmed death ligand 1 (PD-L1) expression with DFS, as measured by immunohistochemistry, was explored retrospectively. Four hundred ninety-eight patients were randomly assigned to receive adjuvant vemurafenib (n = 250) or placebo (n = 248); tumour samples were available for biomarker analysis for approximately 60% of patients. In the pooled biomarker population, placebo-treated patients with <1% CD8+ T cells in the tumour centre had shorter median DFS than those with ≥1% CD8+ T cells (7.7 versus 47.8 months). DFS benefit from vemurafenib versus placebo was greater in patients with <1% CD8+ T cells [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.34–0.92) than in patients with ≥1% CD8+ T cells (HR 0.77; 95% CI 0.48–1.22). Likewise, median DFS was shorter among placebo-treated patients with <5% versus ≥5% PD-L1+ immune cells (IC) in the tumour (7.2 versus 47.8 months). A greater DFS benefit with vemurafenib versus placebo was observed in patients with <5% PD-L1+IC (HR 0.36; 95% CI 0.24–0.56) than in patients with ≥5% PD-L1+IC (HR 0.99; 95% CI 0.58–1.69). The presence of CD8+ T cells and PD-L1+IC are favourable prognostic factors for DFS. Treatment with adjuvant vemurafenib may overcome the poor DFS prognosis associated with low CD8+ T-cell count or PD-L1 expression. NCT01667419 • This study confirms the positive prognosis associated with immune/PD-L1+ tumour infiltrate in BRAF mutant melanoma. • The benefit of adjuvant anti–PD-1 therapy in preventing recurrence is less evident in patients with PD-L1–negative tumours. • Adjuvant vemurafenib may overcome the poor prognosis associated with reduced immune/PD-L1–positive tumour infiltrate. • This study suggests that BRAF inhibition may benefit patients with lower levels of baseline immune infiltrate. [ABSTRACT FROM AUTHOR]

• Neutrophils play important roles throughout the metastatic process. • Tumour progression and invasion are influenced by infiltrating neutrophils. • Signalling from neutrophils can enhance survival of circulating tumour cells. • Neutrophils play a key role in establishing the metastatic niche. The metastasis cascade is complex and comprises several stages including local invasion into surrounding tissue, intravasation and survival of tumour cells in the circulation, and extravasation and colonisation of a distant site. It is increasingly clear that these processes are driven not only by signals within the tumour cells, but are also profoundly influenced by stromal cells and signals in the tumour microenvironment. Amongst the many cell types within the tumour microenvironment, immune cells such as lymphocytes, macrophages and neutrophils play a prominent role in tumour development and progression. Neutrophils, however, have only recently emerged as important players, particularly in metastasis. Here we review the current evidence suggesting a multi-faceted role for neutrophils in the metastatic cascade. [ABSTRACT FROM AUTHOR]

Because of the failure of immunotherapy as single agent in a number of cancers, current clinical trials are focusing on combining immunotherapy with other therapies. The most frequently chosen combination for immunotherapy is chemotherapy. However, almost no preclinical data on this combination is available. Some studies even showed a dismal effect of combining chemotherapy with immunotherapy. Taken into account that each of the therapies chosen in a combination will influence the cancer cells but also immune effector cells as well as immunosuppressive cells, and that these three partners will also interact with each other, launching a combination to the patient without proper immune monitoring and preclinical evidence might be devastating. • Manipulating the order of chemotherapy and immunotherapy can reduce survival. • Thorough immune monitoring prior and during combination treatments is necessary. • More preclinical work is needed before applying combinatorial therapies to patients. [ABSTRACT FROM AUTHOR]

Abstract Cancer immunotherapy has achieved unprecedented success in the treatment of cancer. However, different patients have different responses to immunotherapy. More and more studies have shown that tumor immune heterogeneity has an important influence on the prognosis of cancer. Therefore, understanding the clinical impact of tumor immune infiltration and the regulatory mechanism of RNA molecules is crucial for exploring the pathogenesis of lung adenocarcinoma (LUAD) and the development of immunotherapy protocols.The endogenous competitive RNA hypothesis provides new ideas for studying immune heterogeneity. Therefore, by using the method of immune genomics, this article explores the relationship between immune infiltration and prognosis of patients with lung adenocarcinoma, and found that B-cell immune infiltration highly affects the survival of patients. Through differential analysis, differential mRNAs, lncRNAs and miRNAs were extracted, and 318 differentially expressed mRNAs related to B cell immunity were screened by correlation analysis, and prognosis of patients with COX risk regression model was predicted and analyzed. Through multiple database searches, an immune-related ceRNA regulatory network was constructed, containing 3 key mRNAs, 4 miRNAs, and 50 lncRNAs. Three mRNAs and most miRNAs, lncRNAs, are significantly associated with LUAD prognosis. Bioinformatics analysis of the network showed that LINC 00337 may up-regulate the expression of PBK and KIF23 through competitive binding of has-mir-373 and has-mir-519d. The competitive binding of has-mir-373 and has-mir-372 can up-regulate the expression of SLC7A11. The interaction between these RNAs may have an important regulatory role in the immune infiltration in lung adenocarcinoma, thereby affecting the patient's prognosis and immunotherapy efficacy. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation, which is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. Mounting studies on the essential role of ferroptosis have been published in the progression of solid tumors, metastasis, therapy, and therapy resistance. Studies showed that ferroptosis is a "double-edged sword" in tumor immunity, which means it may have both tumor-antagonizing and tumor-promoting functions. The tumor microenvironment (TME) comprises not only tumor cells but also surrounding immune cells, stromal cells, as well as noncellular components such as the extracellular matrix (ECM), cytokines, growth factors, and extracellular vesicles (EVs). In the complex and diverse condition in TME where tumor cells grow, changes in each constituent may impact tumor destiny differently. Recently, several studies have revealed the interaction between ferroptosis and different constituents in TME. Both tumor cells and nontumor cells have a dual role in tumor immunity and influence tumor progression through ferroptosis. Herein, this review aims at summarizing the role of ferroptosis in tumor immunity based on TME, focusing on the mechanisms of the interaction between the ferroptosis and the different constituents in TME, illuminating how ferroptosis plays its role in promoting or antagonizing tumors by acting with varying components in TME and proposing several questions in immunomodulatory effects of ferroptosis and ferroptosis-associated immunotherapy. • Ferroptosis is a double-edged sword in tumor immunity. • Different cellular components in TME influence tumor progression through ferroptosis. • Both ferroptotic tumor cells and DAMPs released by them have a dual role in tumor immunity. • The major challenge in targeting ferroptosis in tumor treatment is to determine to induce or inhibit ferroptosis in different cells and when to do that. [ABSTRACT FROM AUTHOR]

As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach. We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level. We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition. Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC. [Display omitted] An in-depth characterization of the immune landscape in pancreatic cancer, highlighting features that diverge from other solid cancers, especially lung cancer. [ABSTRACT FROM AUTHOR]

Abstract Dendritic cells (DCs) play key regulatory roles in tumor immunity: increased activity of DCs infiltrating tumor tissues leads to enhancement of tumor immunity. Functions of DCs are also modulated by tumor cell-derived factors. Here, we investigated the effects of low molecular weight oyster polysaccharide (LMW-OPS) on differentiation and function of bone marrow-derived DCs (BMDCs) exposed to a conditioned medium (CM) obtained from spheres of stemness-high colorectal cancer cell lines CMT93 and CT26. The CM containing a detectable level of TGF-β1 was found to down-regulate the surface expression of major histocompatibility complex class II of BMDCs and to inhibit the potency of BMDCs to stimulate T cells. Those suppressions were partly restored and completely restored by addition of anti-TGF-β1 and LMW-OPS, respectively. Production of IFN-γ during allogeneic T cell responses was inhibited by the CM, whereas production of TGF-β1 was augmented by the CM. The IFN-γ profile was also reversed by addition of LMW-OPS. Nuclear translocation of β-catenin, but not that of NF-κB p65, was induced by TGF-β1. NF-κB p65 nuclear translocation, but not β-catenin nuclear translocation, was induced by LMW-OPS. Intraperitoneal injection of LMW-OPS significantly suppressed tumor growth in syngeneic tumor models using CMT93 and CT26 sphere cells, whereas it had no inhibitory effect on the proliferation of either cell line. The results demonstrated that LMW-OPS relieved stemness-high tumor cell-mediated suppression of BMDC function and indicated the in vivo anti-tumor activity of LMW-OPS in which re-stimulation of the activity of DCs infiltrating tumor tissues is presumed to be involved. Highlights • DC generation suppressed by soluble factors of stemness-high colorectal tumor spheres. • Restoration by anti-TGF-β1 of the suppressed DC activity caused by soluble factors. • Restoration by LMW-OPS of the suppressed DC activity caused by soluble factors. • Inhibition of tumor growth after inoculation of tumor sphere cells by LMW-OPS. [ABSTRACT FROM AUTHOR]

Objective To develop criteria for safe and oncologically satisfying liver resection in case of early hepatocellular carcinoma with a 5-year overall survival (OS) similar to liver transplantation. Summary background data Liver resection (LR) and liver transplantation (LT) are potentially curative treatment options for hepatocellular carcinoma. Generally, LT achieves better OS. Due to organ shortage, however not all patients can receive a LT. Methods To decide which patients to resect and which to transplant we have developed biological resection criteria (BRC) as a compound out of mGPS (modified Glascow Prognostic Scale) and the Kings-Score (for HCV cirrhosis). These are based on routine clinical values that reflect both liver function and tumor biology/immunology. Results 276 patients were analyzed. Patients undergoing LR within BRC (inBRC) had a significantly better overall (73.6% vs. 35.4%, (p < 0.001)) and disease-free survival (54.7% vs. 17.2%, (p < 0.001)) as compared to patients outside the BRC (outBRC). The predictive value of BRC was independent of tumor burden. In a subgroup analysis outBRC patients had significantly worse outcome after major resection. In LT patients BRC had no predictive value. Conclusions BRC may be a valuable tool to predict survival after LR for HCC. Patients resected inBRC may achieve comparable survival as LT. LR in outBRC patients are unlikely to be curative. All outBRC patients should be monitored closely for salvage LT. [ABSTRACT FROM AUTHOR]

Highlights • PD-L1 and CD8 expression were significantly higher in p16-positive OPSCC patients. • Higher PD-L1 expression in TC and IC showed better survival than that of lower. • Higher CD8 expression showed better survival than that of lower. • PD-L1 expression in TC and IC can be useful for predicting the response of RT. Abstract Background and purpose To investigate influences of proteins involved with tumor immunity on outcomes of radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC). Material and methods We performed immunohistochemical staining to examine expressions of p16 and proteins involved with tumor immunity in 92 OPSCC patients treated with radiotherapy. Results Patients with abundant infiltrating CD8-positive cells had the significantly better overall survival (OS) rate than patients with fewer CD8-positive cells (p = 0.026). Patients with higher PD-L1 expression in tumor cells (TC 1–3) had a better outcome than those with low PD-L1 expression in tumor cells (TC 0) for both OS (p = 0.019) and progression-free survival (PFS) rate (p = 0.032). Patients with high PD-L1 expression in infiltrating immune cells (IC 3) showed significantly better OS (p = 0.009) and PFS (p = 0.011) than those with low PD-L1 expression (IC 0–2). Patients with p16-negative and IC 3 showed similar OS to patients with p16-positive and IC 0–2. P16-positive tumors had a significantly higher CD8-positive cell infiltration and PD-L1 expression in tumor cells than p16-negative tumors. Conclusions In addition to tumor p16 expression, PD-L1 expression in TC and IC can be useful for predicting the response of OPSCC to radiotherapy. [ABSTRACT FROM AUTHOR]

Abstract Our previous study demonstrated that the incorporation of a tumor antigen into a self-assembling DNA hydrogel, comprised of a DNA containing un-methylated cytosine-phosphate-guanine (CpG) dinucleotides (CpG DNA), efficiently induced antigen-specific tumor immunity after intra-tumoral injection into tumor-bearing mice. We hypothesized that the additional incorporation of immune cells, the target for the antigen and immunostimulatory CpG DNA, would increase the antitumor response. To prove this, immune cells were also encapsulated into the CpG DNA hydrogel and delivered along with the antigen. Mouse dendritic DC2.4 cells maintained their form even after incorporation into the DNA hydrogel. The incorporation of mouse macrophage-like J774.1 cells and RAW264.7 cells into CpG DNA hydrogel did not significantly affect their viability. J774.1, RAW264.7, DC2.4, and mouse bone marrow-derived dendritic cells (BMDCs) were efficiently activated when incorporated into the CpG DNA hydrogel. The CpG DNA hydrogel incorporated with both the tumor antigen and BMDCs effectively induced antigen-specific immune responses, and retarded tumor growth following intradermal administration before and after tumor inoculation without severe local and systemic adverse events. These data indicate that the combined delivery of a tumor antigen and immune cells using an immunostimulatory CpG DNA hydrogel is effective in inducing antigen-specific antitumor immunity. Graphical Abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Exosomes are a group of nano-sized membrane vesicles that transfer proteins, nucleic acids, and lipids to nearby and faraway cells, playing an important role in the intercellular communication within the extracellular environment. Emerging evidences show that exosomes derived from immunocytes, including dendritic cells, T cells, B cells, macrophages, natural killer cells and myeloid-derived suppressor cells, can play an intimate role in the crosstalk among immunocytes in a tumor microenvironment. In this review, we highlight that under tumor conditions, immune cells and tumor cells can be influenced by immunocyte-derived exosomes, resulting in modifications of their phenotype and function. Thus, a better understanding of exosomes derived from different immunocytes would provide novel strategies in generating effective vaccines or improving treatment efficacy in anticancer therapies. [ABSTRACT FROM AUTHOR]

Background: Myeloid derived suppressor cells (MDSC) are heterogeneous immunosuppressive cells with potential predictive and prognostic roles in cancer. The association between MDSC, clinicopathologic factors, and pathologic response in patients with bladder urothelial carcinoma (UC) was explored.Methods: Peripheral blood or tissue were collected from patients with UC undergoing definitive surgery. MDSCs levels were measured in peripheral blood mononuclear cells and fresh tumor tissue. MDSCs were identified by flow cytometry and defined as total MDSC (T-MDSC) CD33+/HLADR-. From this population, 3 subsets were identified: polymorphonuclear-MDSC (PMN-MDSC) defined as CD33+/HLADR-/CD15+/CD14-, monocytic-MDSC (M-MDSC) defined as CD33+/HLADR-/CD15-/CD14+, and immature-MDSC (I-MDSC) defined as CD33+/HLADR-/CD15-/CD14-. MDSC populations were presented as % of live nucleated blood cells. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors, and pathologic complete response (pCR).Results: 85 patients scheduled to undergo cystectomy from February 2015 through Dec 2016 were included. All patients had blood drawn for analysis and 23 patients had residual tumor tissue collected for analysis at the time of surgery. Of these 85, 74 (87%) were men with a median age at diagnosis of 68 (range: 44-87). Pure UC was the most common histology (75%); 28 (35%) patients had prior treatment with intravesical therapy and 36 (42%) were treated with neoadjuvant chemotherapy, primarily gemcitabine plus cisplatin (n = 24). On surgical pathology, 18 (21%) of the patients had pCR, 11 (13%) had positive lymph nodes, and 20 patients (24%) had lymphovascular invasion. Statistically significant associations were found between circulating MDSC levels and pCR rates (P<0.01), absolute neutrophil-lymphocyte ratio (P = 0.008), and histology (P = 0.01). Tumor % M-MDSCs were negatively associated with lymphovascular invasion (P = 0.04). There were no significant correlations between peripheral blood mononuclear cells and tumor MDSC subtypes.Conclusions: Blood and tissue MDSC levels correlate with several clinicopathologic factors and may predict for pCR. Future studies are needed to highlight the role of MDSC in predicting long-term outcomes and to determine the clinical implications of these findings. [ABSTRACT FROM AUTHOR]

Despite different treatment strategies, locally advanced cervical cancer (CC) persists as one of the most incurable cancers among women worldwide. In fact, this setting of patients are at high risk of persistent and recurrent disease. In recent years, researches have investigated immune check-point inhibitors in hopes of determining improved response to therapy with prolongation of survival. We reviewed the published literature and conference proceedings and presented pivotal trials supporting immune check-point inhibitors use in the treatment of CC. [ABSTRACT FROM AUTHOR]

Highly sensitive and selective biosensors for accurate determination of specific protein biomarkers at low levels in serum are a prerequisite for the present healthcare systems. Therefore, here we developed a label-free impedimetric method for tumor necrosis factor-alpha (TNF-α) detection using reduced graphene oxide (RGO) with gold nanoparticles (AuNP) on an indium tin oxide (ITO) microdisk electrodes. The detection mechanism relies on resistance change occurs due to [Fe(CN) 6 ] 3−/4− redox probe movement towards the conductive channels of the AuNP-RGO films gated by the recognition of the target biomarker by its anti-TNF-α antibody. The conductivity of the AuNP-RGO structures enhanced by 10-fold in comparison with bare electrode chips. The observed resistance changes at 2 Hz (ΔR at 2Hz ) enabled the quantification of various concentrations of TNF-α in human serum (C HS-TNF-α ). The antibody-adsorbed electrode showed a good increment of resistance change (ΔR) with additions of antigen concentration. The sensor possesses a linear range of 1–1000 pg/ml had a detection limit of 0.67 pg/ml (38.51 fM) and 0.78 pg/ml (44.83 fM) in PBS and human serum, respectively. [ABSTRACT FROM AUTHOR]

The cytotoxicity and unique tumor-tropic properties of cytokine-induced killer (CIK) cells render them promising in the field of cancer immunotherapy and delivery systems. Here, we report a novel and facile approach to assemble gold nanoclusters (GNCs) into stable and monodispersed nanoparticles (NPs) using Chlorin e6 (Ce6) molecules. Notably, the fluorescence intensity of the GNCs-Ce6 NPs was about 4.5 folds stronger than the GNCs counterparts. The as-prepared GNCs-Ce6 NPs were conjugated with CD3 antibody (Ab) and further employed to label CIK cells to create a CIK cell-based drug delivery system (Ce6-GNCs-Ab-CIK). The Ce6-GNCs-Ab-CIK exhibited high tumor-targeting efficiency and excellent therapeutic efficacy toward MGC-803 tumor-bearing mice. Benefiting from the synergistic therapeutic effect between GNCs-Ce6-Ab NPs and CIK cells, the GNCs-Ce6-Ab-CIK strategy may present an ideal cancer theranostic platform for tumor targeted imaging and combination therapy. [ABSTRACT FROM AUTHOR]

Initially identified as a cell and organ size controller, Hippo pathway turns into a hotspot for researchers. Within recent years, more and more mechanisms about Hippo pathway were uncovered. Even though Hippo signaling has been revealed to exert controversial roles according to different cell context and microenvironment, which is because of its diversified interplays with a great variety of signaling transduction cascades; mechanisms other than size-limitation, however, remain to be elucidated. Recently, a growing number of studies tend to put Hippo on inflammatory and immunological focus: its antimicrobial role in flies, its pro- or anti-inflammation in mammals, as well as its relevance to cancerous immunity. From inflammation to tumor immunogenicity, Hippo has been gradually justified to play a crucial role. This review summarized the latest findings regarding the involvement of Hippo pathway in immunity, and a more comprehensive understanding of Hippo pathway will shed light on clinical translational potential even precision medicine. [ABSTRACT FROM AUTHOR]

The current review focuses on two chemokine–chemokine receptor interactions: CXCL10–CXCR3 and CCL1–CCR8. We show that CXCL10 acts on CD4+ and CD8+ T cells to enhance anti-tumor immunity, and explore the translational perspectives of these findings. As for CCR8 very recently, we identified a novel subset of CCR8+CD4+FOXp3+ regulatory T cells (T reg ) that are major drivers of immune regulation. We observed that one of the four CCR8 ligands, CCL1, produced by these cells, potentiates their suppressive activity via induction of CCR8, FOXp3, CD39, Granzyme-B, and IL-10 in a positive feedback mechanism, making them master drivers of immune regulation. Collectively, this suggests blocking the CCR8–CCL1 interaction, alone or combined with other immune checkpoint inhibitors, as an approach to treat malignant diseases. [ABSTRACT FROM AUTHOR]

Advancement in methodologies for single cell analysis has historically been a major driver of progress in immunology. Currently, high dimensional flow cytometry, mass cytometry and various forms of single cell sequencing-based analysis methods are being widely adopted to expose the staggering heterogeneity of immune cells in many contexts. Here, we focus on mass cytometry, a form of flow cytometry that allows for simultaneous interrogation of more than 40 different marker molecules, including cytokines and transcription factors, without the need for spectral compensation. We argue that mass cytometry occupies an important niche within the landscape of single-cell analysis platforms that enables the efficient and in-depth study of diverse immune cell subsets with an ability to zoom-in on myeloid and lymphoid compartments in various tissues in health and disease. We further discuss the unique features of mass cytometry that are favorable for combining multiplex peptide-MHC multimer technology and phenotypic characterization of antigen specific T cells. By referring to recent studies revealing the complexities of tumor immune infiltrates, we highlight the particular importance of this technology for studying cancer in the context of cancer immunotherapy. Finally, we provide thoughts on current technical limitations and how we imagine these being overcome. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSC) are present in most individuals with cancer where they inhibit adaptive and innate antitumor immunity and are an obstacle to cancer immunotherapies. Chronic inflammation is characteristic of adipose tissue and is a risk factor for the onset and progression of cancer in obese individuals. Because MDSC accumulate in response to inflammation, it has been hypothesized that one of the mechanisms by which obesity promotes malignancy is through the induction of MDSC. This article reviews the data supporting this hypothesis, the role of leptin and fatty acid metabolism in the induction of MDSC, and the surprising finding that although MDSC promote tumor progression, they are protective against some of the metabolic dysfunction associated with obesity. [ABSTRACT FROM AUTHOR]

Tumors are highly heterogeneous structures where malignant cells interact with a large variety of cell populations, including a clinically-relevant immune component. We review and compare the most recent methods designed to analyze and quantify the composition of immune and stromal microenvironment of tumors and discuss their use in identification of patients for high risk of progression. If the impact of the various immune components on patient's relapse share common rules in most malignancies, clear cell renal cell tumors behave differently with regards to immunity. We focus on this specific pathology to show how the tumor interacts with the host's immune system and how this intricate relationship shapes the clinical outcome. [ABSTRACT FROM AUTHOR]

In a previous study, we constructed a MHSP65-TCL anti-lung cancer vaccine with Lewis lung carcinoma TCL plus MHSP65, and illustrated its anti-lung cancer effect through specific and nonspecific anti-tumor immunity. However, TCL contains some immunoinhibit components such as FasL. If this component can be eliminated from TCL, the anti-tumor immunity of MHSP65-TCL constructed with TCL should be improved. In the present study, we knocked down FasL from Lewis lung carcinoma cells and prepared MHSP65-(FasL-/TCL) with this cell line's TCL. After further investigation, MHSP65-(FasL-/TCL) exhibited a better ability to reduce splenocytes apoptosis, promote its activation and secretion of secretingTNF-β, IL-2 compared with MHSP65-(FasL +/TCL). Accordingly, specific and nonspecific antitumor immunity induced by MHSP65-(FasL-/TCL) is stronger than that of MHSP65-(FasL +/TCL). In vivo, MHSP65-(FasL-/TCL) immunization can prolong survival of Lewis lung carcinoma bearing mice. Thus, we report that the anti-lung cancer effect of MHSP65-TCL can be improved by removal of FasL from the TCL. It provides a new route to construct MHSP65-TCL and other antitumor vaccines based on TCL. [ABSTRACT FROM AUTHOR]

Advances from immuno-oncology (IO) are changing the standard of care of many types of cancer, and the paradigm of cancer treatments and drug development is being rewritten on a regular basis. Moreover, an unprecedented number of new investigational agents and companies are entering the field of IO. As such, it has become challenging for oncology physicians conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of the rapidly evolving landscape. To help the key stake holders in the field understand the latest IO landscape, we sought to present an unbiased, neutral, scientifically curated, and timely updated analysis of all the current IO agents in clinical development and the clinical trials testing these agents. We based our analyses on information collected from numerous trusted and publicly available sources. We have developed two databases. One database tracks 2004 IO agents (940 in clinical stage and 1064 in preclinical stage) against 303 targets, from 864 companies; the other tracks 3042 active clinical trials of these agents with a target enrollment of 577 076 patients. This report provides key analyses of these data. Furthermore, we will discuss a number of important and actionable trends in the current IO landscape: a large number of companies developing agents against the same IO targets; a rapid increase in the number of anti-PD-1/L1 combination studies, many of which are testing the same combinations and following inefficient patterns; and a significant increase in the number of small, investigator-initiated studies. For each of the findings, we speculate the causes and discuss a few initiatives that aim to address some of these challenges. Finally, by making these landscape analyses available, we aspire to inform the cancer community as they seek to strive for efficiencies and innovation while avoiding duplication. [ABSTRACT FROM AUTHOR]

cGMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) sensing has emerged as a key regulator of innate immune responses to both exogenous and endogenous DNA. Recent studies reveal critical roles for this pathway in natural antitumor immunity across cancer types as well as in immune checkpoint blockade therapy. However, it is also clear that some tumors evade cGAS–STING-mediated immune responses, and immunomodulatory therapeutics are currently being explored to target this pathway. Finally, we also discuss recent observations that cGAS–STING-mediated inflammation may promote tumor initiation, growth, and metastasis in certain malignancies and how this may complicate the utility of this pathway in therapeutic development. [ABSTRACT FROM AUTHOR]

CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (T TS) cells is unclear. We demonstrate that CD4 T TS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 T TS cells or exhaustion programming, CD4 T TS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 T TS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 T TS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 T TS cells for tumor progression and their potential restoration as therapeutic targets. [Display omitted] • CD4 T TS cells are primed but rapidly "paralyzed" in the dLN during tumor development • Tregs and CTLA4 halt CD4 T TS cell activation, freezing proliferation, and differentiation • CD4 T TS cells retain latent functional capacity to resume tumor infiltration • Overcoming CD4 T TS cells paralysis enhances long-term tumor control How tumor-specific CD4 T cells differentiate and are regulated in response to tumors is not well understood. Guo et al. report that Tregs and CTLA4 rapidly program a dysfunctional CD4 T cell state in the lymph nodes that reduces tumor control. [ABSTRACT FROM AUTHOR]

Stem-like CD8+ T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1+CD8+ T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8+ T cells and ICB response in poorly immunogenic tumors that accumulate TOX+ dysfunctional T cells, but is dispensable for T cell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors. Importantly, improving T cell priming by vaccination or by enhancing antigen presentation on tumors rescues the defective responses of TCF1-deficient CD8+ T cells upon ICB in poorly immunogenic tumors. Our study highlights TCF1's role during the early stages of anti-tumor CD8+ T cell responses with important implications for guiding optimal therapeutic interventions in cancers with low TCF1+CD8+ T cells and low-neo-antigen expression. [Display omitted] • TCF1 regulates the fitness and composition of naive CD8+ T cells • TCF1 promotes optimal tumor-specific CD8+ T cell priming in low-antigenic settings • TCF1-deficient T cells resemble dysfunctional T cells in ICB non-responders • Boosting antigen presentation can overcome dependency on TCF1 for ICB response Escobar et al. uncover that TCF1 expression in CD8+ T cells is required for ICB response in poorly, but not highly, immunogenic tumors. They further show that therapeutic vaccination can rescue ICB response in low antigen-expressing tumors in TCF1-deficient settings. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, namely ADAM17, by enzymatic cleavage of precursor ligands into soluble cytokines and growth factors. Mouse genetic studies have demonstrated that ADAM17 is required for PDAC development. In this study, we evaluated the anti-tumor effects of A9(B8) IgG – the first specific ‘human and mouse cross-reactive’ ADAM17 inhibitory antibody on pancreatic malignant transformation. We found that inhibition of ADAM17 with A9(B8) IgG efficiently suppressed the shedding of ADAM17 substrates both in vivo and in vitro . Furthermore, we demonstrated that administration of A9(B8) IgG significantly suppressed motility in human pancreatic cancer cells and also significantly delayed tumorigenesis in the Pdx1Cre ; Kras G12D ; Trp53 fl/+ PDAC mouse model. Inhibition of ADAM17 with A9(B8) IgG particularly affected the progression of pre-invasive pancreatic lesions to advanced PDAC in mice. Taken together, the preclinical data presented here will provide a starting point for clinical applications of ADAM17 targeted therapy. [ABSTRACT FROM AUTHOR]

In this study, we investigated the clinical benefits of a combination of tumor cryoablation with natural killer (NK) cells therapy and Herceptin for human epidermal growth factor (HER) 2-overexpressing recurrent breast cancer. From May 2015 to May 2016, 48 patients who met the enrollment criteria were assigned to three groups (n = 16): cryoablation group (group I), cryoablation-NK cells therapy group (group II) and cryoablation-NK cells therapy-Herceptin group (group III). Safety and short-term effects were evaluated. All the adverse effects were manageable and acceptable. The three-therapy combination treatment not only yielded good clinical efficacy, it also improved the quality of life; reduced levels of circulating tumor cells (CTCs); reduced carcino-embryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) expression; enhanced immune function significantly. Furthermore, it can resulte in significant prolongation of progression free survival (PFS). This is the first clinical study to demonstrate the benefit of the three-therapy combination of tumor cryoablation, NK cells therapy, and Herceptin for HER2-overexpressing recurrent breast cancer. [ABSTRACT FROM AUTHOR]

Type I interferons (IFN) are increasingly recognized for their role in regulating anti-tumour immune responses. However, chronic activation of these pathways can result in immunosuppression and has been linked to poor responses to genotoxic and radiotoxic therapies. Emerging evidence suggests energy, lipid and amino acid metabolism play an important role in regulating and fine tuning type I IFN responses. Further, dysregulation of these processes has been implicated in the pathogenesis of chronic viral infections and autoimmune disorders. Systematic evaluation of these interrelationships in cancer models and patients may have important implications for the development of targeted IFN based anti-cancer therapeutics with minimal toxicity and limited off target effects. [ABSTRACT FROM AUTHOR]

Introduction TGF-β is an important target for many cancer therapies under development. In addition to suppressing anti-tumor immunity, it has pleiotropic direct pro- and anti- tumor effects. The actions of increased endogenous TGF-β production remain unclear, and may affect the outcomes of anti-TGF-β cancer therapy. We hypothesize that tumor-derived TGF-β (td-TGF-β) plays an important role in maintaining tumor remission by controlling tumor proliferation in vivo, and that decreasing td-TGF-β in the tumor microenvironment will result in tumor progression. The aim of this study was to examine the effect of TGF-β in the tumor microenvironment on the balance between its anti-proliferative and immunosuppressive effects. Methods A murine BALB/c spontaneous colon adenocarcinoma cell line (CT26) was genetically engineered to produce increased active TGF-β (CT26-TGF-β), a dominant-negative soluble TGF-β receptor (CT26-TGF-β-R), or the empty neomycin cassette as control (CT26-neo). In vitro proliferation rates were measured. For in vivo studies, the three cell lines were injected into syngeneic BALB/c mice, and tumor growth was measured over time. Immunodeficient BALB/c nude mice were used to investigate the role of T and B cells. Results In vitro, CT26-TGF-β-R and CT26-TGF-β cells showed increased and suppressed proliferation, respectively, compared to control (CT26-neo), confirming TGF-β has direct anti-tumor effects. In vivo, we found that CT26-TGF-β-R cells displayed slower growth compared to control, likely secondary to reduced suppression of anti-tumor immunity, as this effect was ablated in immunodeficient BALB/c nude mice. However, CT26-TGF-β cells (excess TGF-β) exhibited rapid early growth compared to control, but later failed to progress. The same pattern was shown in immunodeficient BALB/c nude mice, suggesting the effect on tumor growth is direct, with minimal immune system involvement. There was minimal effect on systemic antitumor immunity as determined by peripheral antigen-specific splenocyte type 1 cytokine production and tumor growth rate of CT26-neo on the contralateral flank of the same mice. Conclusion Although TGF-β has opposing effects on tumor growth, this study showed that excessive td-TGF-β in the tumor microenvironment renders the tumor non-proliferative. Depleting excess td-TGF-β may release this endogenous tumor suppressive mechanism, thus triggering the progression of the tumor. Therefore, our findings support cautions against using anti-TGF-β strategies in treating cancer, as this may tip the balance of anti-immunity vs. anti-tumor effects of TGF-β, leading to tumor progression instead of remission. [ABSTRACT FROM AUTHOR]

Summary Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3 + Tregs. Also, pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint. [ABSTRACT FROM AUTHOR]

There is growing evidence supporting the importance of immune microenvironment in cancer development and progression, especially with the rapid development of immunotherapy. Presence of immune cell aggregates in solid tumors has been associated with clinical outcomes, but little is known about the immune microenvironment in oral squamous cell carcinoma (OSCC), which has high morbidity and mortality. Based on our preliminary observation, we hypothesize that there is the presence of tumor-associated immune aggregates (TaIAs) during oral cancer development. Adapting to the dynamic change of the composition of cellular membership and co-evolving with the tumor at invasion fronts, these TaIAs, either pro-inflammatory or immune suppressive, are associated with clinical consequences. With the unique access to a set of prospectively collected, highly annotated OSCC surgical samples and the use of multi-color immunostaining of key immune cells, the confirmation of our hypothesis may shed light of the underlying biology related to OSCC and the knowledge learned can potentially be used to identify prognostic markers, response predictive markers for immunotherapies, as well as novel therapeutic targets. [ABSTRACT FROM AUTHOR]