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Simple Summary: γδ T cells play important roles in cancer immunity. Their rapid activation and cytotoxic nature make them promising candidates for use in cell-based immunotherapies; however, under certain conditions, they can induce pro-tumour functions. Furthermore, upon transformation, γδ T cells can develop into aggressive lymphomas with a poor prognosis and no curative therapeutic options. Here, we provide a comprehensive summary of our current knowledge on the complex roles of γδ T cells in cancer. We discuss their anti- and pro-tumour functions in both solid and blood cancers, highlighting the key subsets involved and their potential utility in anti-cancer immunotherapy. We also discuss the mechanisms of γδ T-cell transformation, summarising the resulting γδ T-cell leukaemia/lymphoma entities and their genetic and molecular profiles, as well as current and future treatment strategies. γδ T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional αβ T cells, γδ T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. γδ T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-γ or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, γδ T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of γδ T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of γδ T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of γδ T-cell transformation, summarising the main γδ T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options. [ABSTRACT FROM AUTHOR]

The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients. [ABSTRACT FROM AUTHOR]

Abstract: Tumor growth results from a delicate balance between intrinsic dysregulation of oncogenes, tumor suppressor and stability genes counteracted by extrinsic defenses composed of immune cells shaping tumor immunogenicity. Although immune subversion might be the ultimate outcome of this process, a complex network of cellular interactions take place eventually leading to tumor specific cognate immune responses. The links between innate and cognate antitumor immunity eliciting protective T cell responses are instigated by cytokines, chemokines and damage associated molecular patterns. The intricate differentiation pathway whereby dendritic cells could undergo an efficient maturation program in the tumor microenvironment appears crucial. We will discuss the role of innate effectors and cancer therapies in the process of defense against tumor cells. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DCs) play a crucial role in linking innate and adaptive immunity and, thus, in the generation of a protective immune response against both infectious diseases and tumors. The ability of DCs to prime and expand an immune response is regulated by signals acting through soluble mediators, mainly cytokines and chemokines. Understanding how cytokines influence DC functions and orchestrate the interactions of DCs with other immune cells is strictly instrumental to the progress in cancer immunotherapy. Herein, we will illustrate how certain cytokines and immune stimulating molecules can induce and sustain the antitumor immune response by acting on DCs. We will also discuss these cytokine–DC interactions in the light of clinical results in cancer patients. [Copyright &y& Elsevier]

Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation. It is efficacious against many primary skin tumors and cutaneous metastases. Using different imidazoquinoline species, distinct functions of TLR7 and TLR8 have been discovered. The predominant antitumoral mode of action of these agents is TLR7/8-mediated activation of the central transcription factor nuclear factor-κB, which leads to induction of proinflammatory cytokines and other mediators. Cutaneous dendritic cells are the primary responsive cell type and initiate a strong Th1-weighted antitumoral cellular immune response. Recent research has shown that dendritic cells themselves acquire direct antitumoral activity upon stimulation by imiquimod. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of TLR7/8. The proinflammatory activity of imiquimod, but not resiquimod, appears to be augmented by suppression of a regulatory mechanism, which normally limits inflammatory responses. This is achieved independently of TLR7/8 through interference with adenosine receptor signaling pathways. Finally, at higher concentrations imiquimod exerts Bcl-2- and caspase-dependent proapoptotic activity against tumor cells.Oncogene (2008) 27, 190–199; doi:10.1038/sj.onc.1210913 [ABSTRACT FROM AUTHOR]

Apoptotic cell death is initiated by a morphologically homogenous entity that was considered to be non-immunogenic and non-inflammatory in nature. However, recent advances suggest that apoptosis, under certain circumstances, can be immunogenic. In particular, some characteristics of the plasma membrane, acquired at preapoptotic stage, can cause immune effectors to recognize and attack preapoptotic tumor cells. The signals that mediate the immunogenicity of tumor cells involve elements of the DNA damage response (such as ataxia telangiectasia mutated and p53 activation), elements of the endoplasmic reticulum stress response (such as eukaryotic initiation factor 2α phosphorylation), as well as elements of the apoptotic response (such as caspase activation). Depending on the signal-transduction pathway, tumor cells responding to chemotherapy or radiotherapy can express ‘danger’ and ‘eat me’ signals on the cell surface (such as NKG2D ligands, heat-shock proteins and calreticulin) or can secrete/release immunostimulatory factors (such as cytokines and high-mobility group box 1) to stimulate innate immune effectors. Likewise, the precise sequence of such events influences the ‘decision’ of the immune system to mount a cognate response or not. We therefore anticipate that the comprehension of the mechanisms governing the immunogenicity of cell death will have a profound impact on the design of anticancer therapies.Cell Death and Differentiation (2008) 15, 3–12; doi:10.1038/sj.cdd.4402269; published online 16 November 2007 [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cells (pDCs), as well as myeloid dendritic cells (mDCs), have a dual role not only in initiating immune responses but also in inducing tolerance to exogenous and endogenous antigens. Tumour antigens originate from endogenous self-antigens, which are poorly immunogenic and also subject to change during tumour progression. In general, tumour antigens derived from apoptotic cells are captured by immature mDCs, antigen presentation by which is most likely to result in immune tolerance. In contrast, tumour antigens may be taken up by pDCs through Toll-like receptor 9 (TLR9) via receptor-mediated endocytosis. TLR9-dependent activation of pDCs results in the secretion of pro-inflammatory cytokines such as interleukin (IL)-12 and type I interferons (IFNs) through a MyD88-dependent pathway. Type I IFNs also activate mDCs for T-cell priming. Although pDCs recruited to the tumour site are implicated in facilitating tumour growth via immune suppression, they can be released from the tumour as a result of cell death caused by primary systemic chemotherapy, and can then be activated through TLR9. Thus, synergistically with mDCs, pDCs may also play a crucial role in mediating cancer immunity. In this review, the potential functional duality and plasticity of pDCs mediated by TLR9 ligation in cancer immunity will be discussed. [ABSTRACT FROM AUTHOR]

Abstract: Suppressor/regulatory T cells were first shown to have an impact on cancer progression in experimental tumor models during the 1970s. However, the lack of specific markers hindered mechanistic investigations, and skepticism grew in the scientific community due to variability in cell populations and reported functions. The identification of regulatory CD4+CD25+ T cells has generated a great deal of renewed interest in cells that have immune regulatory properties. This article will provide a brief historical review of suppressor T cells and cancer, experimental and clinical evidence that CD4+CD25+ natural regulatory T cells play a role in cancer progression, and briefly discuss current strategies to inhibit these cells in an effort to enhance cancer immunotherapy. [Copyright &y& Elsevier]

Four reaction-diffusion cellular neural network (R-D CNN) models are set up based on the differential equation models for the growths of effector cells and cancer cells, and the model of the immune response to cancer proposed by Allison et al. The CNN models have different reaction-diffusion coefficients and coupling parameters. The R-D CNN models may provide possible quantitative interpretations, and are good in agreement with the in vitro experiment data reported by Allison et al. [ABSTRACT FROM AUTHOR]

Summary: The search for target molecules on tumor cells eliciting strong immune responses in cancer patients has been pursued over decades. Growth factors and their respective receptors were discovered as suitable targets for passive or active immunotherapy approaches. Monoclonal antibodies directed against some of these targets like the proto-oncogene HER2/neu have become an accepted standard of therapy in the clinical management of subgroups of HER2/neu overexpressing breast cancer patients and in other malignancies. Antibodies against multiple other target molecules like epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), etc., are explored in ongoing trials in order to enter clinical practice in the near future. More recently, potent techniques have been developed to identify cancer antigens eliciting spontaneous immune responses in cancer patients. Cancer vaccination strategies targeting some of these cancer antigens have also been developed, and are maturing for clinical application. With reliable immunomonitoring techniques in place it has been shown that vaccination with some of these cancer antigens may induce strong integrated (humoral and cellular) immune responses in antigen-positive cancer patients. A prominent example is the cancer testis (CT-) antigen NY-ESO-1, which is expressed in 30% of all breast cancers. NY-ESO-1 is one of the most immunogenic human cancer antigens known to date. The aim of ongoing clinical trials is to induce or augment preexisting immune responses in cancer patients with strong NY-ESO-1 positive disease. There is preliminary evidence that patients with strong NY-ESO-1-specific immune responses have more favorable courses of disease. In several clinical phase I trials targeting HER2/neu it was shown that antigen-specific T cell responses could be induced. Another new cancer antigen explored for cancer vaccination is the breast differentiation antigen NY-BR-1, expressed in 70% of all tested primary breast cancers. Although this cancer antigen is still in preclinical testing, its strong and restricted pattern of expression in breast cancer makes it a promising target for clinical development. For all cancer vaccines there is mounting evidence that the stage of disease to be targeted is minimal residual disease or in adjuvant settings. [Copyright &y& Elsevier]

Short-term fasting (STF), using a low caloric, low protein fasting mimicking diet (FMD), appears to be a promising strategy to enhance chemotherapy-based cancer efficacy, while potentially alleviating toxicity. Preclinical results suggest that enhanced tumor immunity and decreased growth signaling, via lowering of circulating insulin and insulin growth factor 1 (IGF-1) levels form the potential underlying mechanisms. STF may boost anti-tumor responses by promoting tumor immunogenicity and decreasing local immunosuppression. These findings warrant further studies focused on the combination of STF, not only with chemotherapy, but also with immunotherapy to evaluate the full range of benefits of STF in cancer treatment. Here, we delineate the underlying anticancer mechanisms of fasting. We summarize preclinical evidence of STF boosting antitumor immunity and alleviating immunosuppression, as well as the clinical findings reporting the immunomodulatory effects of STF during various cancer treatments, including immunotherapy.

Introduction: Factors underlying antitumor immunity in pancreatic cancer (PC) are poorly understood. We hypothesized that not neoantigen quantity, but quality, is related to immune cell infiltration and survival., Methodology: We performed genomic and transcriptomic profiling of paired normal, tumor tissue of 13 patients with PC with distinct survival times. Additionally, neoantigens prediction and immunological profiling were performed., Results: The proportion of neoantigens with a low similarity-to-self score was higher in short-term survivors ( p < 0.0001), while mutational load and burden, similarity-to-known-pathogens, and immunogenicity of neoantigens were not associated with immune cell infiltration or survival., Discussion: No tumor mutational load or neoantigen quantity, but low similarity-to-self score, was associated with immune cell infiltration and survival., Competing Interests: SR: A shareholder of Adjutec B.V. SOD: A shareholder of Adjutec B.V. MB: Boston Scientific (Consultant, support for industry and investigator-initiated studies), Cook Medical (Consultant, support for industry and investigator-initiated studies), Pentax Medical (Consultant, support for investigator-initiated studies), Mylan (Support for investigator-initiated studies), ChiRoStim (Support for investigator-initiated studies). LB served as a paid consultant for Bristol-Myers Squibb in Pathologist Advisory Board PD-L1 CPS testing in upper GI cancer. The remaining 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 Levink, Brosens, Rensen, Aberle, Olde Damink, Cahen, Buschow, Fuhler, Peppelenbosch and Bruno.)

Though single tumor immunotherapy and radiotherapy have significantly improved the survival rate of tumor patients, there are certain limitations in overcoming tumor metastasis, recurrence, and reducing side effects. Therefore, it is urgent to explore new tumor treatment methods. The new combination of radiotherapy and immunotherapy shows promise in improving therapeutic efficacy and reducing recurrence by enhancing the ability of the immune system to recognize and eradicate tumor cells, to overcome tumor immune tolerance mechanisms. Nanomaterials, as new drug-delivery-system materials of the 21st century, can maintain the activity of drugs, improve drug targeting, and reduce side effects in tumor immunotherapy. Additionally, nanomaterials, as radiosensitizers, have shown great potential in tumor radiotherapy due to their unique properties, such as light, heat, electromagnetic effects. Here, we review the mechanisms of tumor immunotherapy and radiotherapy and the synergy of radiotherapy with multiple types of immunotherapies, including immune checkpoint inhibitors (ICIs), tumor vaccines, adoptive cell therapy, and cytokine therapy. Finally, we propose the potential for nanomaterials in tumor radiotherapy and immunotherapy., 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 Yu, Wang, He, Shao, Liu, Xiang, Yang, Zeng, He, Ma, Wang and Liu.)

Macrophages of the M2 phenotype in malignant tumors significantly aid tumor progression and metastasis, as opposed to the M1 phenotype that exhibits anti-cancer characteristics. Raising the ratio of M1/M2 is thus a promising strategy to ameliorate the tumor immunomicroenvironment toward cancer inhibition. We report here that tumor necrosis factor superfamily-15 (TNFSF15), a cytokine with anti-angiogenic activities, is able to facilitate the differentiation and polarization of macrophages toward M1 phenotype. We found that tumors formed in mice by Lewis lung carcinoma (LLC) cells artificially overexpressing TNFSF15 exhibited retarded growth. The tumors displayed a greater percentage of M1 macrophages than those formed by mock-transfected LLC cells. Treatment of mouse macrophage RAW264.7 cells with recombinant TNFSF15 led to augmentation of the phagocytic and pro-apoptotic capacity of the macrophages against cancer cells. Mechanistically, TNFSF15 activated STAT1/3 in bone marrow cells and MAPK, Akt and STAT1/3 in naive macrophages. Additionally, TNFSF15 activated STAT1/3 but inactivated STAT6 in M2 macrophages. Modulations of these signals gave rise to a reposition of macrophage phenotypes toward M1. The ability of TNFSF15 to promote macrophage differentiation and polarization toward M1 suggests that this unique cytokine may have a utility in the reconstruction of the immunomicroenvironment in favor of tumor suppression., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

tRNA-derived fragments (tRFs) constitute a novel class of small non-coding RNA cleaved from tRNAs. In recent years, researches have shown the regulatory roles of a few tRFs in cancers, illuminating a new direction for tRF-centric cancer researches. Nonetheless, more specific screening of tRFs related to oncogenesis pathways, cancer progression stages and cancer prognosis is continuously demanded to reveal the landscape of the cancer-associated tRFs. In this work, by combining the clinical information recorded in The Cancer Genome Atlas (TCGA) and the tRF expression profiles curated by MINTbase v2.0, we systematically screened 1,516 cancer-associated tRFs (ca-tRFs) across seven cancer types. The ca-tRF set collectively combined the differentially expressed tRFs between cancer samples and control samples, the tRFs significantly correlated with tumor stage and the tRFs significantly correlated with patient survival. By incorporating our previous tRF-target dataset, we found the ca-tRFs tend to target cancer-associated genes and onco-pathways like ATF6-mediated unfolded protein response, angiogenesis, cell cycle process regulation, focal adhesion, PI3K-Akt signaling pathway, cellular senescence and FoxO signaling pathway across multiple cancer types. And cell composition analysis implies that the expressions of ca-tRFs are more likely to be correlated with T-cell infiltration. We also found the ca-tRF expression pattern is informative to prognosis, suggesting plausible tRF-based cancer subtypes. Together, our systematic analysis demonstrates the potentially extensive involvements of tRFs in cancers, and provides a reasonable list of cancer-associated tRFs for further investigations., 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 Zhou, Cui and Zhou.)

Introduction: Antidiabetic drug metformin exerts various antitumor effects on different cancers. Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer and new treatment strategy is required. In this study, we performed a comprehensive gene expression analysis of ESCC cell lines treated with metformin, which provided helpful information on the antitumor effects of metformin in ESCC. Next, we selected a promising gene among them and examined its effects on ESCC properties., Methods: We examined metformin-induced mRNA expression changes in two human ESCC cell lines by performing next-generation sequencing (NGS) and pathway analysis. Heat shock protein family A (Hsp70) member 6 (HSPA6) expression in surgical specimens obtained from 83 ESCC patients who underwent curative operations was evaluated immunohistochemically and analyzed., Results: Metformin upregulated mRNA expression of the many genes, including HSPA6, a cancer immune-related gene, and inhibited mRNA expression of the other many genes. Pathway analysis indicated major canonical pathways and upstream regulators related to metformin. The result indicated HSPA6 as a promising biomarker. HSPA6 expression correlated with disease-free survival (DFS) of the patients with all stage ESCC (p = 0.021), especially with stage I/II ESCC (p < 0.001). With stage III, low HSPA6 expression was not associated with poor DFS (p = 0.918). Multivariate analysis indicated that independent low HSPA6 expression was an independent poor prognostic factor of stage I/II ESCC (p < 0.001). However, HSPA6 expression did not correlate with the clinicopathological characteristics, including age, sex, tumor depth, lymph node metastasis, tumor stage, and tumor markers of the patients with stage I/II ESCC., Conclusions: This NGS analysis detected prospective candidate genes, including HSPA6. Our results indicate that HSPA6 is a promising biomarker of the recurrence risk of stage I/II ESCC. Further studies on HSPA6 would lead to better treatment., (© 2022 S. Karger AG, Basel.)

Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8+ T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8+ T cell responses. [Display omitted] • Secreted gelsolin (sGSN) inhibits DNGR-1 binding to F-actin • sGSN dampens DNGR-1-dependent cross-presentation of dead cell-associated antigens • sGSN impairs DNGR-1-dependent cDC1-mediated anti-tumor immunity • Low sGSN expression and mutations in FABPs correlate with cancer patient survival The secreted gelsolin component of the plasma actin-scavenging system impairs the ability of the receptor DNGR-1 to recognize dead cells and selectively dampens cross-presentation of tumor antigens by type 1 dendritic cells, acting as a barrier to anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Current immuno-oncology primarily focuses on adaptive cellular immunity mediated by T lymphocytes. The other important lymphocytes, B cells, are largely ignored in cancer immunotherapy. B cells are generally considered to be responsible for humoral immune response to viral and bacterial infections. The role of B cells in cancer immunity has long been under debate. Recently, increasing evidence from both preclinical and clinical research has shown that B cells can also induce potent anti-cancer immunity, via humoral and cellular immune responses. Yet it is unclear how to efficiently integrate B cell immunity in cancer immunotherapy. In the current perspective, anti-tumor immunity of B cells is discussed regarding antibody production, antigen presentation, cytokine release and contribution to intratumoral tertiary lymphoid structures. Afterwards, immunosuppressive regulatory phenotypes of B cells are summarized. Furthermore, strategies to activate and modulate B cells using nanomedicines and biomaterials are discussed. This article provides a unique perspective on "PLAN B" (promoting and leveraging anti-tumor B cell immunity) using nanomedicines and biomaterials for cancer immunotherapy. This is envisaged to form a new research direction with the potential to reach the next breakthrough in immunotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The highly conserved homology cassette family (HOX) as well as 18 referenced long non-coding antisense transcripts (HOXATs) play vital roles in the development of some cancers. Nevertheless, their expression patterns as well as their association with cancer prognosis and the tumor microenvironment (TME) in pan-cancers are still unclear. Here, based on public databases, the expression levels of HOXATs, their prognostic potentials, and correlation with tumor mutation burden (TMB), immune cell infiltration, immune subtype, immune response-related genes, and stemness scores corresponding to 33 tumor types were analyzed systematically using R language. The results of the analysis indicated that different cancer tissues show different HOXAT expression profiles. Further, HOXAT expression showed association with cancer prognosis and immune and stemness regulation. Gene set enrichment analysis also demonstrated that HOXATs participate in cancer- and immune-related pathways, and based on their expression levels, HOTAIRM1 and HOXB-AS1 showed potential involvement in oncogenesis as well as possible involvement in immune regulation across a variety of cancer types. Further investigation also confirmed a significantly higher expression of HOXB-AS1 in GBM than in lower grade glioma tissues. Importantly, in vitro cell function experiments indicated that HOXB-AS1 supports cancer stem cell and plays a fundamental role in glioma metastasis. In conclusion, our results provide valuable resources that can guide the investigation of the mechanisms related to the role of HOXATs in cancers as well as therapeutic analysis in this regard., 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 Shao, Ding, Guo, Xing, Huo, Wang, Xu and Guo.)

Neuroligin 2 (NLGN2) is a well-recognized transmembrane scaffolding protein that functions in synapse development and neuronal signal transduction. It has recently been implicated in multiple diseases of peripheral ectodermal origin. However, the potential roles of NLGN2 in tumors remain ill-defined. The aim of this study was to determine the clinical relevance and prognostic value of NLGN2 in breast cancer. To this end, breast cancer datasets were extracted from TCGA and other public databases, and subjected to Kaplan-Meier potter for survival analysis, GEPIA2 for assessing the immunological relevance of NLGN2 and THPA for identifying its subcellular localization. The in-silico results were further validated by immunohistochemistry analysis of in-house tumor tissue specimens. NLGN2 was identified as a prognostic factor in breast cancer subtypes, and its high expression correlated to a favorable survival outcome. Moreover, NLGN2 overexpression in breast cancer was significantly associated with large tumor size, lymph node metastasis, late TNM stage, and high histological grade. Interestingly, there was a significant correlation between the expression level of NLGN2 and the immunomodulatory molecules, along with increased interstitial infiltration of lymphocytes. Furthermore, NLGN2 was predominantly localized in the mitochondria of breast cancer cells. In conclusion, NLGN2 has a prognostic role and immunoregulatory potential in breast cancer, and its functions likely have a mitochondrial basis. It is a promising therapeutic target in breast cancer and should be explored further., 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 Zhang, Sun, Wu and Huang.)

APOBEC proteins can deaminate cytosine residues in DNA and RNA. This can lead to somatic mutations, DNA breaks, RNA modifications, or DNA demethylation in a selective manner. APOBECs function in various cellular compartments and recognize different nucleic acid motifs and structures. They orchestrate a wide array of genomic and epigenomic modifications, thereby affecting various cellular functions positively or negatively, including immune editing, viral and retroelement restriction, DNA damage responses, DNA demethylation, gene expression, and tissue homeostasis. Furthermore, the cumulative increase in genomic and epigenomic editing with aging could also, at least in part, be attributed to APOBEC function. We synthesize our cumulative understanding of APOBEC activity in a unifying overview and discuss their genomic and epigenomic impact in physiological, pathological, and technological contexts., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Long noncoding RNAs (lncRNAs) are versatile in functions and can regulate cancer development, including the modulation of cancer immunity. Immune-related lncRNA signatures predicting prognosis have been reported in multiple cancers, but relevant studies in gastric cancer (GC) are still lacking., Methods: We performed a comprehensive analysis using TCGA and Immport databases and identified an immune-related lncRNA signature by univariate and multivariate Cox regression analysis. qRT-PCR and immunohistochemistry assays were used for further validation. KEGG and GO analysis and ceRNA network establishment were carried out to explore the regulatory functions., Results: We first identified an immune-related lncRNA signature, which can stratify gastric cancer patients into high- and low-risk subgroups and the high-risk cases frequently suffered from shorter overall survival time. Next, we validated the reliability of the lncRNA signature in an independent 75 gastric cancer samples and demonstrated that the three-year survival rate in high-risk patients was only 30.8% versus 66.5% in low-risk counterparts. Functional exploration indicated that the lncRNA signature might participate in multiple cancer-associated processes including cell adhesion and migration, cytokine-receptor interaction and immune evasion. Additionally, we observed that high-risk samples tended to form an immunosuppressive microenvironment, which had more M2-polarized macrophages and Tregs, but fewer CD8 effector T cells within tumors. Moreover, we found that PD-1 and PD-L1 were dramatically upregulated in a subset of high-risk patients with abundant M2 and Treg infiltration, implying these patients may benefit from anti-PD-1 and PD-L1 immunotherapy., Conclusions: These results showed that the immune-related lncRNA signature had a prominent capacity to predict overall survival and the immune status of microenvironment in gastric cancer. Our findings may be useful for the risk-stratification management and provide a valuable clue to identify proper patients potentially benefit from immune checkpoint therapy in gastric cancer., 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. The handling editor FL declared a shared parent affiliation with the authors EM, YW, XX, ZW, and JZ at the time of the review., (Copyright © 2021 Ma, Hou, Wang, Xu, Wang and Zhao.)

Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME., 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 Subtil, Cambi, Tauriello and de Vries.)

Immunosurveillance and immunoscavenging prompted by preoperative chemoradiotherapy (CCRT) may contribute to improve local control and increase survival outcomes for patients with locally advanced rectal cancer (LARC). In this study, we investigated several genotypes of pattern recognition receptors (PRRs) and their impact on therapeutic efficacy in LARC patients treated with CCRT. We found that homozygosis of formyl peptide receptor 1 (FPR1) (E346A/rs867228) was associated with reduced 5-year overall survival (OS) by Kaplan-Meier analysis (62% vs. 81%, p = 0.014) and multivariate analysis [hazard ratio (HR) = 3.383, 95% CI = 1.374-10.239, p = 0.007]. Moreover, in an animal model, we discovered that the FPR1 antagonist, Boc-MLF (Boc-1), reduced CCRT therapeutic efficacy and decreased cytotoxic T cells and T effector memory cells after chemoradiotherapy treatment. Pharmacologic inhibition of FPR1 by Boc-1 decreased T lymphocyte migration to irradiated tumor cells. Therefore, these results revealed that the FPR1 genotype participates in CCRT-elicited anticancer immunity by reducing T lymphocytes migration and infiltration, and that the FPR1-E346A CC genotype can be considered an independent biomarker for chemo- and radiotherapy outcomes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by regulating the duration and intensity of the immune response. Furthermore, immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response. Based on substantial physiological analyses as well as preclinical and clinical studies, checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers. In the last few years, extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines (TCMs). The main advantage of TCMs and natural medicine is that they usually contain multiple active components, which can act on multiple targets at the same time, resulting in additive or synergistic effects. The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest. For example, Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals, and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion. Furthermore, many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers. Therefore, it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs. In this review, we focus on research progress in the field of immune checkpoints based on three topics: (1) immune checkpoint targets and pathways, (2) development of novel immune checkpoint-based drugs, and (3) application of immune checkpoints in the development of TCMs., Competing Interests: The authors report no conflicts of interest., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)