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Immunity in the tumor microenvironment plays a central role in tumor development. Cytotoxic immune cells act against tumors, while tumors manage to trigger immunosuppressive mechanisms for defense. One bout of physical exercise acutely regulates the immune system inducing short-term redistribution of immune cells among body organs. Repeated acute immune cell mobilization with continuing exercise training results in long-term adaptations. These long-term exercise-induced changes in the immune system arise both in healthy and in diseased populations, including cancer patients. Recent preclinical studies indicate that physical exercise may have a positive impact on intra-tumoral immune cell processes, resulting in tumor suppression. This short narrative review describes the effect of physical exercise on tumor growth as detected via changes in tumor immunity. Research evidence shows that exercise may improve tumor-suppressive functions and may reduce tumor-progressive responses and mechanisms of immune cells, controlling tumor development. Specifically, it seems that exercise in rodents triggers shifts in tumor infiltration of macrophages, neutrophils, natural killer cells, cytotoxic and regulatory T lymphocytes, resulting in tumor suppression. These recent promising data suggest that physical exercise could be combined with anticancer immunotherapies, although exercise parameters like intensity, duration, and frequency need to be evaluated in more detail. More research is needed to investigate the effect of exercise in other immune cell subtypes and their possible connection with tumor growth, whilst information from human tumors is also required.

Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.

Immunotherapies based on T cells have gained significant success in the treatment of diverse cancers, however, several limitations also exist, including low response, acquired resistance and severe side effects, which lead to unfavorable outcomes. Recent studies found that traditional therapies, radiotherapy and/or chemotherapy may affect the immune condition in situ and cause abscopal effect, which may improve the response of immunotherapies, enhance the efficiency, and reduce the untoward effect. Here, we review the mechanisms uncovering the cancer immunotherapy and immunogenic effects of radiotherapy and chemotherapy, aiming to highlight the principles underlying the therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy and ultimately guide better designs for future synergistic cancer therapies. [ABSTRACT FROM AUTHOR]

Disulfiram (DSF), a drug widely used to control alcoholism, which has anticancer activity by inducing apoptosis in a copper (Cu)-dependent manner. Numerous evidences from mouse experiments indicated that some anti-cancer agents of chemotherapeutic drugs favor the induction of immunogenic cancer cell death (ICD) leading to tumor-specific immune responses. However, whether DSF could induce the colorectal tumor cells death and the mechanism involved in ICD regulatory remains elusive. The main objective of this study was to elucidate the effect of DSF/Cu on the apoptosis of colorectal cancer (CRC) cells and the expression of the two major ICD markers in CRC cells: calreticulin (CRT) and heat shock proteins (HSP) 70. Firstly, the toxicity of DSF/Cu in HCT116, SW620 and HCT8 cells was assayed by MTT. Flow cytometry was utilized to detect the apoptosis effects. The effects of DSF/Cu on the expression of ICD-related molecules in tumor tissues were further verified in the CRC xenograft mouse model. The results showed that DSF/Cu increase apoptosis of these three cells in a dose dependent manner and significantly inhibited the proliferation at the concentration range from 0.05 to 1.6 μM. Furthermore, the expression of CRT and HSP70 on the cell surface also increased. The rate of transplanted tumors grew slowly, and the expression of CRT and HSP70 in colorectal cancer tissues was increased after treated with DSF/Cu. In conclusion, our results show that DSF/Cu exerts anti-colorectal cancer and its underlying mechanisms are associated with the enhancement of molecules expression of cell ICD. These results provide experimental evidence and theory basis of therapy for developing the DSF/Cu as the drug for CRC. Image 1015 • DSF/Cu has high cytotoxicity effect in colorectal cancer. • Treatment with DSF/Cu can induce immunogenic cell death in CRC cell lines. • DSF/Cu exerts anti-cancer and its underlying mechanisms are associated with the enhancement of molecules expression of cell ICD. [ABSTRACT FROM AUTHOR]

Since the realization that immature myeloid cells are powerful modulators of the immune response, many studies on "myeloid-derived suppressor cells" (MDSCs) have documented their ability to promote tumor progression in melanoma and other cancers. Whether MDSCs are induced solely pathologically in tumorigenesis, or whether they also represent physiological immune control mechanisms, is not well-understood, but is particularly important in the light of ongoing attempts to block their activities in order to enhance anti-tumor immunity. Here, we briefly review studies which explore (1) how best to identify MDSCs in the context of cancer and how this compares to other conditions in humans; (2) what the suppressive mechanisms of MDSCs are and how to target them pharmacologically; (3) whether levels of MDSCs with various phenotypes are informative for clinical outcome not only in cancer but also other diseases, and (4) whether MDSCs are only found under pathological conditions or whether they also represent a physiological regulatory mechanism for the feedback control of immunity. Studies unequivocally document that MDSCs strongly influence cancer outcomes, but are less informative regarding their relevance to infection, autoimmunity, transplantation and aging, especially in humans. So far, the results of clinical interventions to reverse their negative effects in cancer have been disappointing; thus, developing differential approaches to modulate MSDCs in cancer and other diseases without unduly comprising any normal physiological function requires further exploration. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) efficiently process and present antigens to T cells, and by integrating environmental signals, link innate and adaptive immunity. DCs also control the balance between tolerance and immunity, and are required for T-cell mediated anti-tumor immunity. One subset of classical DCs, cDC1, are particularly important for eliciting CD8 T cells that can kill tumor cells. cDC1s are superior in antigen cross-presentation, a process of presenting exogenous antigens on MHC class I to activate CD8+ T cells. Tumor-associated cDC1s can transport tumor antigen to the draining lymph node and cross-present tumor antigens, resulting in priming and activation of cytotoxic T cells. Although cross-presenting cDC1s are critical for eliciting anti-tumor T cell responses, the role and importance of other DC subsets in anti-tumor immunity is not as well-characterized. Recent literature in other contexts suggests that critical crosstalk between DC subsets can significantly alter biological outcomes, and these DC interactions likely also contribute significantly to tumor-specific immune responses. Therefore, antigen presentation by cDC1s may be necessary but not sufficient for maximal immune responses against cancer. Here, we discuss recent advances in the understanding of DC subset interactions to maximize anti-tumor immunity, and propose that such interactions should be considered for the development of better DC-targeted immunotherapies. [ABSTRACT FROM AUTHOR]

Highlights • CD40 × HER2 ScDb fragment was constructed by SOE-PCR and expressed using a prokaryotic expression system. • CD40 × HER2 ScDb could inhibit the proliferation of tumor cells by stimulating tumor-specific immunoreactions in vivo and vitro experiments. • CD40 × HER2 ScDb could inhibit the proliferation of tumor cells by blocking the HER2-related signaling pathway. Abstract Our aim was to construct a CD40×HER2 single chain diabody (ScDb) and determine its tumor-specific immune activation and anti-HER2 function. Overlap extension-polymerase chain reaction was applied in the construction of ScDb, and the protein was expressed with the pET28a (+)-Rosetta prokaryotic expression system. Soluble ScDb was purified by a nickel-nitrilotriacetic acid column. Dendritic cells (DC) was stimulated by ScDb and inhibited 4T1 cells proliferation in vitro. In 4T1 tumor mice model, lymphocyte infiltration was prominently detected in ScDb group, Caspase-3 expression was significantly upregulated. ScDb was labeled using quantum dots. Immunofluorescence assay indicated ScDb exhibited high affinity to HER2. T6-17 cells were inhibited by ScDb in vitro. The phosphorylation and expression levels of AKT, ERK were markedly decreased. In T6-17 tumor mice model. Compared to CD40 ScFv, HER2 ScFv and normal saline groups, tumor volume diminished significantly in ScDb group, and tumor cells showed extensive deformation, and pervasive karyopyknosis and karyorrhexis were found. In the present study, we successfully constructed a ScDb fragment and expressed it using a prokaryotic expression system. The in vivo and in vitro experimental results indicated that ScDb could inhibit the proliferation of tumor cells by stimulating the tumor-specific immunoreaction and blocking the HER2-related signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths worldwide. Despite immune checkpoints based immunotherapy highlights a new therapeutic strategy and achieves a remarkable therapeutic effect in various types of malignant tumors. Pancreatic cancer is one of the non-immunogenic cancers and is resistant to immunotherapy. Programmed death ligand 1 (PD-L1) is expressed on the surface of tumor cells and its level is a key determinant of the checkpoint immunotherapy efficacy. Here, we reported that the specific inhibitor of histone deacetylase 3 (HDAC3) decreased the protein and mRNA level of PD-L1 in pancreatic cancer cells. Furthermore, we showed that HDAC3 was critical for PD-L1 regulation and positively correlated with PD-L1 in PDAC patient specimens. Finally, we demonstrated that HDAC3/signal transducer and activator of transcription 3 (STAT3) pathway transcriptionally regulated PD-L1 expression. Collectively, our data contributes to a better understanding of the function of HDAC3 in cancer immunity and the regulatory mechanism of PD-L1. More importantly, these data suggest that the HDAC3 inhibitors might be used to improve immunotherapy in pancreatic cancer. [ABSTRACT FROM AUTHOR]

T cell "exhaustion" describes a state of late-stage differentiation usually associated with active prevention of functionality via ligation of negative signaling receptors on the cell surface, and which can be reversed by blocking these interactions. This contrasts with T cell "senescence," which has been defined as a state that is maintained by intrinsic internal cell signaling (caused by DNA damage or other stresses) and which can be reversed pharmacologically. Interventions to alleviate these two different categories of inhibitory pathways may be desirable in immunotherapy for cancer and possibly certain infectious diseases, but reciprocally inducing and maintaining these states, or some properties thereof, may be beneficial in organ transplantation and autoimmunity. Even under physiological non-pathological conditions, T cell exhaustion and senescence may play a role in the retention of T cell clones required for immunosurveillance, and prevent their loss via elimination at the Hayflick limit. This essay briefly reviews T cell exhaustion in contrast to replicative senescence, and circumstances under which their modulation may be beneficial. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are increasingly known to be important in cancer as they directly interact with the cell cycle, proliferation pathways and microbiome balance. Moreover, lncRNAs regulate the immune system: they do not directly encode proteins of innate or adaptive immunity, but regulate immune cell differentiation and function, such as dendritic cell activity, T cell ratio and metabolism. The result of this complex interaction is that lncRNAs regulate cancer processes through a complex multimodal system involving immunity, metabolism and infection. The possible functions of lncRNAs and their roles in the regulation of cancer immunity will be reported and discussed in the present review. Recent studies showed their function as regulators in the tumour microenvironment (TME), epithelial–mesenchymal transition, microbiota, metabolism and immune cell differentiation. However, there is not much knowledge regarding their roles in cancer immunity regulation. Thus, the main aim of this review is to describe lncRNAs that have specifically been associated with immunity, the immune cycle and the TME. This review gives an overview of the complex interaction between lncRNAs and cancer immunity. Regulation involves metabolism, host microbiota and the epithelial–mesenchymal transition and leads to cancer dissemination. However, there is not much knowledge regarding the role of lncRNAs in cancer immunity regulation. Here, we describe the regulatory role of lncRNAs on the immune cycle and the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to comprehensively characterize head and neck squamous cell carcinoma (HNSCC) arising in young patients (<45 years old). Methods: We performed immunohistochemistry, silver, and fluorescence in situ hybridization using samples obtained from 396 radically resected cases among 1787 HNSCCs. Results: Young age HNSCCs occurred in 10.9% (194/1787) and were most common in the oral tongue (50.5%). They revealed distinctively lower frequency of p16 positivity, high c‐MET expression, MET copy number gain, and lower pan‐Trk expression. PD‐L1 positivity in tumor cells and ICOS+ tumor infiltrating lymphocytes (TILs) were higher in the young age. Perineural invasion, PD‐L1 positivity, and higher ratio of CD163+ tumor infiltrating macrophages to CD8 + TILs were determined to be independent factors for poor progression‐free survival. Conclusion: Characterizing these features of young age HNSCC may help to identify the underlying pathogenesis and to improve patient outcome through different treatment strategies. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small noncoding RNAs that function in post-transcriptional regulation of gene expression. Dysregulation of miRNAs has been reported in different stages of cancer development and progression. This dysregulation results in different miRNA profiles between cancer and normal tissues. Many studies have shown a significant correlation between miRNA profile and cancer diagnosis and prognosis. Additionally, since a single miRNA regulates multiple mRNA targets, miRNAs dysregulation can affect several pathways involved in cancer development. Finally, due to their regulatory role in immune cell development, many recent studies have reported that certain miRNAs play key roles in cancer immunology. In this brief review, we discuss the role of miR-21 and miR-375 in the RAS pathway as well as their role in cancer diagnosis and progression, along with the role of other select miRNAs in cancer immune surveillance. [ABSTRACT FROM AUTHOR]

Highlights • The immunogenic property of CTAs can result in the production of autoantibodies in cancer patients. • A highly multiplex array technology was used to identify autoantibodies to CTAs in plasma of NSCLC patients. • Reactivity against many CTAs was detected in NSCLC but also in less extent in plasma of patients with benign lung diseases. • We confirmed the reactivity of six CTAs that were exclusively reactive in NSCLC plasma. Abstract Objectives Cancer-testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. Materials and methods To comprehensively analyze autoantibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. Results Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analyzed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against cancer-testis antigen family 47; member A (CT47A) genes, P antigen family member 3 (PAGE3), variable charge X-linked (VCX), melanoma antigen family B1 (MAGEB1), lin-28 homolog B (LIN28B) and chromosome 12 open reading frame 54 (C12orf54) were only found in NSCLC patients at a frequency of 1%–4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients. Conclusion We identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets. [ABSTRACT FROM AUTHOR]

Abstract The critical role of angiogenesis in promoting tumor growth and metastasis has been well established scientifically, and consequently blocking this pathway as a therapeutic strategy has demonstrated great clinical success for the treatment of cancer. The holy grail however, has been the identification of patients who derive significant survival benefit from this class of agents. Here we attempt to delineate the diverse mechanisms related to anti-VEGF including its role as an anti-vascular, anti-angiogenic or an anti-permeability factor and review the most promising predictive biomarkers interrogated in large clinical trials, that identify patients who may derive significant survival advantage with VEGF inhibition. Lastly, we describe the function of VEGF as an immunomodulator and illustrate the evidence for anti-VEGF in reprogramming the tumor milieu from an immunosuppressive to an immune permissive microenvironment in human cancers, thus elucidating the role of anti-VEGF as an optimal combination partner for immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Highlights • Accumulating evidence points at a protective role of the vagus nerve in cancer pathologies. • The vagus nerve modulates innate and adaptive immune responses. • Vagus nerve stimulation shows antitumor effects by attenuating TNFα secretion by TAMs. • Vagus nerve stimulation arrests MDSC proliferation and enhances the efficacy of DCs. • Vagal signaling alters T-cell responsiveness in normal and pathophysiological conditions. Abstract Accumulating evidence points to a beneficial effect ofvagus nerve activity in tumor development. The vagus nerve is proposed to slow tumorigenesis because of its anti-inflammatory properties mediated through ACh and the α7nAChR. Since α7nAChRs are widely expressed by many types of immune cells we hypothesized that the vagus nerve affects the tumor microenvironment and anticancer immunity. We found direct evidence in studies using animal cancer models that vagus nerve stimulation alters immunological responses relevant to the tumor microenvironment. Also studies in pathologies other than cancer suggest a role for the vagus nerve in altering immunological responses relevant to anticancer immunity. These results provide a rationale to expect that vagus nerve stimulation, in combination with conventional cancer treatments, may improve the prognosis of cancer patients by promoting anticancer immunity. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) was originally identified as an anti-tumour cytokine. However, there is increasing evidence that it has important roles in the tumour microenvironment (TME) in facilitating cancer progression. TGF-β actively shapes the TME via modulating the host immunity. These actions are highly cell-type specific and complicated, involving both canonical and non-canonical pathways. In this review, we systemically update how TGF-β signalling acts as a checkpoint regulator for cancer immunomodulation. A better appreciation of the underlying pathogenic mechanisms at the molecular level can lead to the discovery of novel and more effective therapeutic strategies for cancer.

Lack of MHC-II is emerging as a causal factor in cancer immune evasion, and the development of small-molecule MHC-II inducers is an unmet clinical need. Here, we identified three MHC-II inducers, including pristane and its two superior derivatives, that potently induce MHC-II expression in breast cancer cells and effectively inhibit the development of breast cancer. Our data suggest that MHC-II is central in promoting the immune detection of cancer to increase the tumor infiltration of T cells and enhance anti-cancer immunity. By discovering the malonyl/acetyltransferase (MAT) domain in fatty acid synthase (FASN) as the direct binding target of MHC-II inducers, we demonstrate that evasion of immune detection and cancer metabolic reprogramming are directly linked by fatty acid-mediated MHC-II silencing. Collectively, we identified three MHC-II inducers and illustrated that lack of MHC-II caused by hyper-activated fatty acid synthesis to limit immune detection is a potentially widespread mechanism underlying the development of cancer. [Display omitted] • Three MHC-II inducers, including pristane and its derivatives, have been identified • MHC-II inducers effectively inhibit the development of breast cancer in animal models • MHC-II inducers fire up the tumor microenvironment by promoting immune detection • FASN-mediated MHC-II silencing underlies cancer cell escape from immune detection Huang et al. identified three small-molecule MHC-II inducers that effectively increase tumor-infiltrating T cells and enhance anti-cancer immunity, with FASN-mediated MHC-II expression as the underlying mechanism. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) have been reported to involve in diverse biological processes, including tumor immunity. Since lncRNAs are expressed with high cell-type specificity, investigation of lncRNAs at the single-cell level will unveil the cell-type-specific functions of lncRNAs. However, at the single-cell level, a systematic pan-cancer analysis of lncRNA functions in tumor immune microenvironments (TIMEs) remains lacking. Here, we performed pan-cancer single-cell profiling of lncRNA functions in TIMEs and developed a tool, scLNC, tailored for lncRNA functional characterization at the single-cell level. scLNC enabled the comparison of lncRNA function from the levels of lncRNA-mRNA pairs, lncRNA regulatory unit activity and unit function in a cell-type-specific manner. Applying scLNC, our analysis depicted the cross-tumor and tumor-specific lncRNA regulatory profiles in the T cell subtypes and revealed the new regulatory units that lncRNAs established in tumor-infiltrating T cells, particularly in the tumor-enriched T cells. We further characterized the activity and functional alternations of lncRNAs through their regulatory units. Overall, our findings suggested that lncRNAs played an important role in the regulation of cytokine production, cell activation and migration in tumor-enriched T cells and further in immunotherapy. • Developed a tool, scLNC, specifically designed for the lncRNA regulatory network at the single-cell level. • Pan-cancer analysis of lncRNA functions in tumor-infiltrating T cells at the single-cell level. • LncRNAs established new regulatory units in tumor-infiltrating T cells, particularly in the tumor-enriched T cells. • Unveiled the activity and functional alternations of lncRNAs through their regulatory units in tumor-infiltrating T cells. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A), the most common internal modification in RNA, can be regulated by three types of regulators, including methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Recently, immunotherapy represented by immune checkpoint blocking has increasingly become an effective cancer treatment, and increasing shreds of evidence show that m6A RNA methylation affects cancer immunity in various cancers. Until now, there have been few reviews about the role and mechanism of m6A modification in cancer immunity. Here, we first summarized the regulation of m6A regulators on the expression of target messenger RNAs (mRNA) and their corresponding roles in inflammation, immunity response, immune process and immunotherapy in various cancer cells. Meanwhile, we described the roles and mechanisms of m6A RNA modification in tumor microenvironment and immune response by affecting the stability of non-coding RNA (ncRNA). Moreover, we also discussed the m6A regulators or its target RNAs which might be used as predictor of cancer diagnosis and prognosis, and shed light on the potentiality of m6A methylation regulators as therapeutic targets in cancer immunity. [Display omitted] • Summarized the role and mechanism of m6A modification target mRNAs in cancer immunity process and response. • Summarized the regulation of m6A regulators on the expression of ncRNAs and their corresponding roles in cancer immunity. • Discussed the potentiality of m6A methylation regulators as biomarkers for cancer diagnosis, and prognosis. [ABSTRACT FROM AUTHOR]

Awareness of the importance of immunity in controlling cancer development triggered research into the impact of its key oncogenic drivers on the immune response, as well as their value as targets for immunotherapy. At the heart of tumour suppression is p53, which was discovered in the context of viral infection and now emerges as a significant player in normal and cancer immunity. Wild-type p53 (wt p53) plays fundamental roles in cancer immunity and inflammation. Mutations in p53 not only cripple wt p53 immune functions but also sinisterly subvert the immune function through its neomorphic gain-of-functions (GOFs). The prevalence of mutant p53 across different types of human cancers, which are associated with inflammatory and immune dysfunction, further implicates mutant p53 in modulating cancer immunity, thereby promoting tumorigenesis, metastasis and invasion. In this review, we discuss several mutant p53 immune GOFs in the context of the established roles of wt p53 in regulating and responding to tumour-associated inflammation, and regulating innate and adaptive immunity. We discuss the capacity of mutant p53 to alter the tumour milieu to support immune dysfunction, modulate toll-like receptor (TLR) signalling pathways to disrupt innate immunity and subvert cell-mediated immunity in favour of immune privilege and survival. Furthermore, we expose the potential and challenges associated with mutant p53 as a cancer immunotherapy target and underscore existing therapies that may benefit from inquiry into cancer p53 status.

Glycodelin is a kind of glycoprotein expressed in secretory endometrium, pregnancy deciduas, and amniotic fluid originally, which is vital for the maintenance of normal human reproductive activities. Recent researches have reported that glycodelin is specifically expressed in various malignancies, including female-specific cancers such as endometrial cancer, ovarian cancer and breast cancer, and non-gender specific cancers including lung cancer, and colon cancer, and glycodelin expression correlates with the diagnosis and prognosis of cancer patients. This review focuses on the expression of glycodelin in different cancers and its role in cancer development and progression. Glycodelin possesses the abilities to regulate cancer cell proliferation, differentiation, and invasion, promote cancer angiogenesis, and modulate the differentiation and function of immune cells including T cells, dendritic cells, monocyte-macrophages, natural killer cells and B cells participating in cancer development. The expression of glycodelin can be regulated by stromal cells, lysophosphatidic acid, histone deacetylase inhibitors, and relaxin. In summary, glycodelin is a promising biomarker for the diagnosis and prognosis of cancer patients, and depending on its distinct immunoregulatory effects, glycodelin can be a prospective target for cancer immunotherapy.

Background: N 6 -methyladenosine (m 6 A) is the most abundant epitranscriptomic modification of RNA, which can affect RNA metabolism and protein translation. The m 6 A modification plays a critical role in cancer development, including hepatocellular carcinoma (HCC). Despite several m 6 A-related signatures in HCC, most of them lack the necessary validation and the reliability is still elusive., Methods: Differentially expressed genes (DEGs) in the Cancer Genome Atlas were comprehensively analyzed to identify m 6 A signature associated with HCC prognosis. Gene set enrichment analysis, tumor mutation burden (TMB), immune infiltration, and therapeutic response were evaluated. Importantly, mass spectrometry proteomics and multiplex immunofluorescence assays were performed for validation., Results: The m 6 A-related protein-coding gene signature was established, which can divide HCC into high-/low-risk subgroups with markedly different overall survival (OS) and clinical stages. Furthermore, we validated its reliability and robustness in our 101 independent HCC specimens using proteomic detection and confirmed that our signature readily identified high-risk HCC patients with 3-year survival rates of 44.1% vs. 71.8% in the low-risk group. Functional analysis indicated that the high-risk group might stimulate the cell cycle and activate oncogenic pathways such as MAPK, mTOR, and VEGF, whereas the low-risk group mainly regulated amino acid, fatty acid, and drug metabolism. Additionally, the high-risk group had more TMB, upregulated immune checkpoint molecule expression, including PD-1, CTLA4, TIM3, and LAG3, and preferentially formed an immunosuppressive microenvironment. Accordingly, potential therapeutic responses showed that high-risk patients were potentially sensitive to inhibitors targeting the cell cycle and MAPK signaling, with patients possibly benefiting from immunotherapy. Moreover, multiplex immunofluorescence assays indicated that high-risk HCC samples displayed distinct immunosuppressive features, with abundant M2-polarized macrophages and T-regulatory cell infiltration., Conclusion: The m 6 A signature had a prominent capacity to evaluate OS and characterize the tumor immune microenvironment of HCC, which may serve as a useful approach for risk stratification management and provide a valuable clue to choosing rational therapeutic strategies., 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 © 2023 Ma, Li, Shen, Gu, Zhang, Li, Zhao and Wang.)

Background: SERPINE1 , a serine protease inhibitor involved in the regulation of the plasminogen activation system, was recently identified as a cancer-related gene. However, its clinical significance and potential mechanisms in pan-cancer remain obscure. Methods: In pan-cancer multi-omics data from public datasets, including The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), and online web tools were used to analyze the expression of SERPINE1 in different cancers and its correlation with prognosis, genetic alteration, DNA promoter methylation, biological processes, immunoregulator expression levels, immune cell infiltration into tumor, tumor mutation burden (TMB), microsatellite instability (MSI), immunotherapy response and drug sensitivity. Further, two single-cell databases, Tumor Immune Single-cell Hub 2 (TISCH2) and CancerSEA, were used to explore the expression and potential roles of SERPINE1 at a single-cell level. The aberrant expression of SERPINE1 was further verified in clear cell renal cell carcinoma (ccRCC) through qRT-PCR of clinical patient samples, validation in independent cohorts using The Gene Expression Omnibus (GEO) database, and proteomic validation using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Results: The expression of SERPINE1 was dysregulated in cancers and enriched in endothelial cells and fibroblasts. Copy number amplification and low DNA promoter methylation could be partly responsible for high SERPINE1 expression. High SERPINE1 expression was associated with poor prognosis in 21 cancers. The results of gene set enrichment analysis (GSEA) indicated SERPINE1 involvement in the immune response and tumor malignancy. SERPINE1 expression was also associated with the expression of several immunoregulators and immune cell infiltration and could play an immunosuppression role. Besides, SERPINE1 was found to be related with TMB, MSI, immunotherapy response and sensitivity to several drugs in cancers. Finally, the high expression of SERPINE1 in ccRCC was verified using qRT-PCR performed on patient samples, six independent GEO cohorts, and proteomic data from the CPTAC database. Conclusion: exhibits aberrant expression in various types of cancers and is associated with cancer immunity and tumor malignancy, providing novel insights for individualized cancer treatment.SERPINE1 exhibits aberrant expression in various types of cancers and is associated with cancer immunity and tumor malignancy, providing novel insights for individualized cancer treatment., 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 © 2023 Li, Li, Xu, Li, Hu, Li, Yu, Wang and Gao.)

Imbalanced immune homeostasis in cancer microenvironment is a hallmark of cancer. Increasing evidence demonstrated that long non-coding RNAs (lncRNAs) have emerged as key regulatory molecules in directly blocking the cancer immunity cycle, apart from activating negative regulatory pathways for restraining tumor immunity. lncRNAs reshape the tumor microenvironment via the recruitment and activation of innate and adaptive lymphoid cells. In this review, we summarized the versatile mechanisms of lncRNAs implicated in cancer immunity cycle, including the inhibition of antitumor T cell activation, blockade of effector T cell recruitment, disruption of T cell homing, recruitment of immunosuppressive cells, and inducing an imbalance between antitumor effector cells (cytotoxic T lymphocytes, M1 macrophages, and T helper type 1 cells) versus immunosuppressive cells (M2 macrophages, T helper type 2 cells, myeloid derived suppressor cells, and regulatory T cells) that infiltrate in the tumor. As such, we would highlight the potential of lncRNAs as novel targets for 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 © 2023 Zhan and Xian.)

Background: Toll-like receptors (TLRs) are the key sensors of innate immunity for triggering immune responses against infections. TLRs are well known to be expressed and activated in innate immune cells, such as macrophage and dendritic cells, but we and others have found that some TLRs are also functional in epithelial cells. However, the role of an epithelial TLR in prostate cancer remains elusive., Methods: TLR5 expression in messenger RNA and protein level in prostate cancer was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The activation of TLR5 signaling in epithelial cells was detected upon nuclear factor-κB activation by luciferase assay and western blot analysis, and proinflammatory cytokine activation by RT-qPCR. Distinguishing between the TLR5 and NLRC4 pathways, both recognizing flagellin, is determined by small interfering RNA and proinflammatory cytokine activation. The role of TLR5 in prostate cancer was analyzed by IHC and bioinformatics using a general and single-cell database., Results: In the present study, we show that TLR5, among other TLRs, is exceedingly expressed in human prostate cancer cells. This cancer epithelial cell TLR5 functions to activate the TLR5 signaling pathway in human prostate cancer cells, as it does with innate immune cell TLR5. The bacterial protein flagellin induces a robust immune response in prostate cancer cells in a TLR5-dependent but NLRC4-independent manner. TLR5 is highly expressed in prostate cancer patient specimens, and high TLR5 expression in prostate cancer patients indicates a favorable prognosis., Conclusions: TLR5, as an innate immunity receptor, is a functional TLR in human prostate cancer epithelial cells. TLR5 plays an important role in prostate cancer development and is a new potential prognosis biomarker. TLR5 may represent a novel immunotherapy target against prostate cancer., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Aim Clear-cell renal cell carcinoma (ccRCC) is characterized with underlying genetic disorders and the role of low density lipoprotein receptor-related protein 1 (LRP1) in ccRCC is unknown. Method An in silico exploratory analysis using multiple public genetic datasets was used to establish association between LRP1 expression and clinicopathological parameters. Associations of interest were validated using 155 ccRCC samples using immunohistochemistry. Results LRP1 was overexpressed in tumor compared with normal kidney tissue. Increased LRP1 expression in ccRCC was associated with advanced stage, grade and worsened overall survival and progression-free survival. Functional annotation indicated an immune-modulatory role of LRP1 in ccRCC. LRP1 expression was significantly correlated with expressions of PBRM1, SETD2, and KDM5C. Positive correlations between LRP1 and pro-angiogenic factors ERAP1, SCG2, STAB1, and RUNX1 were observed. LRP1 expression was positively correlated with PD-L2 level. Negative correlations between LRP1 and anti-angiogenic factors EMCN and IL18 were observed. LRP1 expression was not associated with microvessel density (MVD) yet was negatively correlated with tumor-infiltrating lymphocytes (TIL). Conclusion LRP1 is associated with worsened prognosis in ccRCC and is related to cancer immune modulation. LRP1-targeted therapy can be of therapeutic potential. [ABSTRACT FROM AUTHOR]

Recent years have seen a number of regulatory approvals for immune oncology or immunotherapies based on their ability to enhance antitumor immune responses. Nevertheless, the majority of patients remain refractory to these treatments; hence, new therapies that augment current immunotherapies are required. Innate immune receptors that recognize nucleic acids are potent activators of subsequent T‐cell responses and, as a result, can evoke potent antitumor immune responses. Herein, we present a novel compound N‐{3‐[(1,4′‐bipiperidin)‐1′‐yl]propyl}‐6‐[4‐(4‐methylpiperazin‐1‐yl)phenyl]picolinamide (SINCRO; STING‐mediated interferon‐inducing and cytotoxic reagent, original) as an anticancer drug that activates the cytosolic DNA‐sensing STING (stimulator of interferon genes) signaling pathway leading to the induction of type I interferon (IFN) genes. Indeed, IFN‐β gene induction by SINCRO is abolished in STING‐deficient cells. In addition to its IFN‐inducing activity, SINCRO shows STING‐independent cytotoxic activity against cancer cells. SINCRO does not evoke DNA double‐strand break or caspase‐3 cleavage. Thus, SINCRO induces cell death in a method different from conventional apoptosis‐inducing pathways. Finally, we provide evidence that giving SINCRO significantly attenuates in vivo tumor growth by both type I IFN‐dependent and independent mechanisms. Thus, SINCRO is an attractive anticancer compound with dual function in that it evokes type I IFN response to promote antitumor immunity as well as inducing tumor cell death. SINCRO may provide a new platform for the development of drugs for effective cancer therapy. [ABSTRACT FROM AUTHOR]

In the tumor microenvironment (TME), cancer cells, stromal cells, and immune cells, along with their extracellular factors, have profound effects on either promoting or repressing anti-cancer immunity. Accumulating evidence has shown the paradoxical intrinsic role of the Forkhead box O (FOXO) family of transcription factors in cancer, which can act as a tumor repressor while also maintaining cancer stem cells. FOXOs also regulate cancer immunity. FOXOs promote antitumor activity through negatively regulating the expression of immunosuppressive proteins, such as programmed death 1 ligand 1 (PD-L1), and vascular endothelial growth factor (VEGF) in tumor cells or stromal cells, which can shape an immunotolerant state in the TME. FOXOs also intrinsically control the anti-tumor immune response as well as the homeostasis and development of immune cells, including T cells, B cells, natural killer (NK) cells, macrophages, and dendritic cells. As a cancer repressor, reviving the activity of Foxo1 forces tumor-infiltrating activated regulatory T (T reg ) cells to egress from tumor tissues. As a promoter of cancer development, Foxo3 and Foxo1 negatively regulate cytotoxicity of both CD8 + T cells and NK cells against tumor cells. In this review, we focus on the complex role of FOXOs in regulating cancer immunity due to the various roles that they play in cancer cells, stromal cells, and immune cells. We also speculate on some possible additional roles of FOXOs in cancer immunity based on findings regarding FOXOs in non-cancer settings, such as infectious disease. [ABSTRACT FROM AUTHOR]

Since the 1920s the gold standard for treating cancer has been surgery, which is typically preceded or followed with chemotherapy and/or radiation, a process that perhaps contributes to the destruction of a patient's immune defense system. Cryosurgery ablation of a solid tumor is mechanistically similar to a vaccination where hundreds of unique antigens from a heterogeneous population of tumor cells derived from the invading cancer are released. However, releasing tumor-derived self-antigens into circulation may not be sufficient enough to overcome the checkpoint escape mechanisms some cancers have evolved to avoid immune responses. The potentiated immune response caused by blocking tumor checkpoints designed to prevent programmed cell death may be the optimal treatment method for the immune system to recognize these new circulating cryoablated self-antigens. Preclinical and clinical evidence exists for the complementary roles for Cytotoxic T-lymphocyte-associated protein (CTLA-4) and PD-1 antagonists in regulating adaptive immunity, demonstrating that combination immunotherapy followed by cryosurgery provides a more targeted immune response to distant lesions, a phenomenon known as the abscopal effect. We propose that when the host's immune system has been "primed" with combined anti-CTLA-4 and anti-PD-1 adjuvants prior to cryosurgery, the preserved cryoablated tumor antigens will be presented and processed by the host's immune system resulting in a robust cytotoxic CD8+ T-cell response. Based on recent investigations and well-described biochemical mechanisms presented herein, a polyvalent autoinoculation of many tumor-specific antigens, derived from a heterogeneous population of tumor cancer cells, would present to an unhindered yet pre-sensitized immune system yielding a superior advantage in locating, recognizing and destroying tumor cells throughout the body. [ABSTRACT FROM AUTHOR]

To assess the effect of low‑molecular‑weight polysaccharides from Agaricus blazei Murrill (ABP‑AW1) as an immunoadjuvant therapy for type 1 T‑helper (Th1) responses in tumorigenesis, C57BL/6 mice were inoculated subcutaneously with ovalbumin (E.G7‑OVA). After 3, 10 and 17 days, the mice were immunized with PBS, OVA alone, or OVA and ABP‑AW1, at low (50 μg), intermediate (100 μg) or high (200 μg) doses. Tumor growth was examined and compared among the groups, as were the following parameters: Splenocyte viability/proliferation, peripheral blood CD4+/CD8+ T cell ratio, serum OVA‑specific IgG1 and IgG2b, secretion of interleukin (IL)‑2 and interferon (IFN)‑γ, and IFN‑γ production on a single cell level from cultured splenocytes. Tumor growth in mice treated with OVA and ABP‑AW1 (100 or 200 μg) was significantly slower, compared with in the other groups at the same time-points. OVA with 100 or 200 μg ABP‑AW1 was associated with a higher number of total splenocytes, a higher ratio of peripheral blood CD4+/CD8+ T‑lymphocytes, higher serum levels of OVA‑specific Th1‑type antibody IgG2b and greater secretion of the Th1 cytokines IL‑1 and IFN‑γ from splenocytes. ABP‑AW1 is a promising immunoadjuvant therapy candidate, due to its ability to boost the Th1 immune response when co‑administered with a cancer vaccine intended to inhibit cancer progression. [ABSTRACT FROM AUTHOR]

Hippo signaling has a pivotal role in organ size control, tissue regeneration, and cancer. Recent studies have demonstrated critical functions of Hippo signaling in cancer immunity, innate immune responses against pathogens, and autoimmune diseases, refreshing our understanding of the implications of this pathway in the context of disease and therapy design. [ABSTRACT FROM AUTHOR]

The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57-70, 67; Cell 144:646-674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823-837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response. [ABSTRACT FROM AUTHOR]

We evaluated the expression patterns of p16, which is used as a surrogate marker of HPV infection in head and neck squamous cell carcinoma ( HNSCC), in regard to their biological and prognostic implications. p16 expression patterns and infiltrated immune cells were analyzed through immunohistochemistry of p16, CD3, CD8, PD-1, FOXP3, and CD163 on surgically resected HNSCCs (n = 393). Patterns of p16 immunoexpression were defined as STRONG (strong, diffuse expression in cytoplasm, and nucleus in >70% of tumor cells), MARGINAL (expression restricted to tumor margins), MOSAIC (ragged, discontinued expression), NUCLEAR (expression in nuclei only), and ABSENT (no expression). The STRONG pattern was more frequent in the oropharynx, and the MARGINAL pattern was noted only in the oral cavity. MOSAIC and NUCLEAR patterns were noted at variable sites. No two patterns of p16 expression showed the same immune cell composition of CD3+ T cells, CD8+ cytotoxic T cells, PD-1+ T cells, FOXP3+ regulatory T cells, and CD163+ macrophages. In overall and disease-free survival analyses, the STRONG pattern showed the most favorable prognosis, while the NUCLEAR pattern had the worst prognosis. HNSCC anatomical sites, tumor-related immune cell components, and patient outcomes were associated with p16 expression patterns. Each architectural pattern of p16 expression may be related to different biological and prognostic phenotypes. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to determine changes in laboratory data for cancer patients receiving Korean medicine (KM) care, with a focus on patients’ functional status, cancer-coagulation factors and cancer immunity. Methods: We conducted an observational study of various cancer patients in all stages admitted to the East-West Cancer Center (EWCC), Dunsan Korean Hospital of Daejeon University, from Mar. 2011 to Aug. 2011. All patients were under the center’s multi-modality Korean-medicine-based inpatient cancer care program. The hospitalization stay at EWCC ranged from 9 to 34 days. A total of 80 patients were followed in their routine hematologic laboratory screenings performed before and after hospitalization. Patients were divided into three groups depending on the status of their treatment: prevention of recurrence and metastasis group, Korean medicine (KM) treatment only group, and combination of conventional and KM treatment group. The lab reports included natural killer (NK) cell count (CD16 + CD56), fibrinogen, white blood cell (WBC), lymphocytes, monocytes, neutrophil, red blood cell (RBC), hemoglobin, platelet, Erythrocyte Sedimentation Rate (ESR), and Eastern Cooperative Oncology Group (ECOG) performance status. Results: With a Focus on patients’ functional status, cancer-coagulation factors and cancer immunity, emphasis was placed on the NK cell count, fibrinogen count, and ECOG scores. Data generally revealed decreased fibrinogen count, fluctuating NK cell count and decreased ECOG, meaning improved performance status in all groups. The KM treatment only group showed the largest decrease in mean fibrinogen count and the largest increase in mean NK cell count. However, the group’s ECOG score showed the smallest decrease, which may be due to the concentration of late-cancer-stage patients in that particular group. Conclusions: Multi-modality KM inpatient care may have positive effect on lowering the cancer coagulation factor fibrinogen, but its correlation with the change in the NK cell count is not clear.

Patient-derived tumor organoids (PDOs) represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture models. We have established PDOs from various human tumors to accurately and efficiently recapitulate the tissue architecture and function. Molecular targeted therapies with remarkable efficacy are currently in use against various tumors. Thus, there is a need for in vitro functional-potency assays that can be used to test the efficacy of molecular targeted drugs and model complex interactions between immune cells and tumor cells to evaluate the potential for cancer immunotherapy. This study represents an in vitro evaluation of different classes of molecular targeted drugs, including small-molecule inhibitors, monoclonal antibodies, and an antibody-drug conjugate, using lung PDOs. We evaluated epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) inhibitors using a suitable high-throughput assay system. Next, the antibody-dependent cellular cytotoxicity (ADCC) activity of an anti-HER2 monoclonal antibody was evaluated to visualize the interactions of immune cells with PDOs during ADCC responses. Moreover, an evaluation system was developed for the immune checkpoint inhibitors, nivolumab and pembrolizumab, using PDOs. Our results demonstrate that the in vitro assay systems using PDOs were suitable for evaluating molecular targeted drugs under conditions that better reflect pathological conditions.

The Hippo pathway was originally identified as an evolutionarily-conserved signaling mechanism that contributes to the control of organ size. It was then rapidly expanded as a key pathway in the regulation of tissue development, regeneration, and cancer pathogenesis. The increasing amount of evidence in recent years has also connected this pathway to the regulation of innate and adaptive immune responses. Notably, the Hippo pathway has been revealed to play a pivotal role in adaptive immune cell lineages, as represented by the patients with T- and B-cell lymphopenia exhibiting defective expressions of the pathway component. The complex regulatory mechanisms of and by the Hippo pathway have also been evident as alternative signal transductions are employed in some immune cell types. In this review article, we summarize the current understanding of the emerging roles of the Hippo pathway in adaptive immune cell development and differentiation. We also highlight the recent findings concerning the dual functions of the Hippo pathway in autoimmunity and anti-cancer immune responses and discuss the key open questions in the interplay between the Hippo pathway and the mammalian immune system.

Colorectal cancer (CRC) is one of the most common causes of cancer deaths worldwide and the number of CRC patients is increasing progressively. Despite the improvement of the surgical techniques and chemotherapy, we have not completely overcome this disease yet due to the metastases. Therefore, understanding the mechanisms through which metastasis occurs is important for overcoming CRC. Normal host cells in the tumor microenvironment, such as macrophages and fibroblasts, have been reported to promote the growth of CRCs. Although neutrophils were originally considered to have defensive functions against tumor cells, it has been revealed that some populations of neutrophils, called as tumor-associated neutrophils (TANs), have tumor-supportive functions. The plasticity between tumor-suppressive and -supportive neutrophils are regulated by transforming growth factor (TGF)-β and Interferon-β signaling. Some studies have demonstrated that TANs promote the spread of cancer cells to distant organs. TANs contribute to the tumor invasion and angiogenesis through the production of matrix metalloproteinase-9 (MMP9), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) in the primary and metastatic sites. Neutrophils also promotes tumor cell dissemination by capturing circulating tumor cells using neutrophil extracellular traps and promote their migration to distant sites. The neutrophil-to-lymphocyte ratio is a well-defined predictive marker for CRC patients. In this review, we highlight the molecular signaling between TANs and CRC cells and the possibility of TANs as a potential target for cancer therapy.