Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with p < 5 × 10-8 associated with at least one of the cancer types at p < 10-3 and one of the autoimmune/autoinflammatory diseases at p < 10-3. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) was each strongly correlated (Spearman's ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. Conclusions: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 and LAT as possible targets for cancer immunotherapy.

Immunoglobulin G4 (IgG4), a unique subclass of IgG antibodies, plays diverse roles in human health and disease. Its distinct features, such as Fab-arm exchange and specific mutations, confer reduced effector functions compared to other IgG subclasses. In health, IgG4 responses contribute to immune tolerance, particularly in the context of allergen-specific immunotherapy (AIT), where they can mediate tolerance to environmental antigens, inhibit IgE-dependent mast cell degranulation, and compete with IgE for allergen binding. This helps in attenuating allergic symptoms and is associated with increased levels of allergen-specific IgG4. However, in disease scenarios, the role of IgG4 is complex. IgG4 lacks complement fixation and, thus, shows a reduced ability to activate immune effector pathways, it was initially thought to be protective against autoimmune diseases. However, emerging evidence suggests that it can contribute to pathology. For instance, IgG4 autoantibodies against specific antigens can aggravate conditions in certain autoimmune disorders. In some cancers, it may play a role in immune evasion, with higher levels correlating with poor patient survival, albeit in others, its exact function remains elusive. Overall, understanding the precise role of IgG4 in various physiological and pathological conditions is crucial for developing targeted therapeutic strategies and improving patient outcomes.

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV antigen-specific antibody responses associated with clinical outcomes, we comprehensively characterized antibody responses to the complete EBV proteome using a custom protein microarray in 56 patients with EBV-associated lymphoma who received EBVST infusions in phase 1 clinical trials. Responders (nonprogressors) and nonresponders (progressors) had distinct antibody profiles against EBV. Twenty-five immunoglobulin G (IgG) antibodies were significantly elevated in higher levels in nonresponders than in responders at 3 months after EBVST infusion. Ten of these remained significant after adjustment for sex, age, and cancer type, including LMP2A (4 variants), BGRF1/BDRF1 (2 variants), LMP1, BKRF2, BKRF4, and BALF5. Random forest analysis identified these 10 IgG antibodies as key predictors of clinical response. Paired analyses using blood samples collected at both before infusion and 3 months after EBVST infusion indicated an increase in the mean antibody level for 6 other anti-EBV antibodies (IgG [BGLF2, LF1, and BGLF3]; IgA [BGLF3, BALF2, and BBLF2/3) in nonresponders. Overall, our findings suggest that these EBV-directed antibodies as potential serological markers for predicting clinical responses to EBVST infusions and as therapeutic targets for immunotherapy in EBV-positive lymphomas. These trials were registered at www.clinicaltrials.gov as #NCT01555892 (Cytotoxic T-Lymphocytes for EBV-positive Lymphoma [GRALE]), #NCT02973113 (Nivolumab With Epstein Barr Virus Specific T Cells [EBVSTS], Relapsed/Refractory EBV Positive Lymphoma [PREVALE]), and #NCT02287311 (Most Closely Matched 3rd Party Rapidly Generated LMP, BARF1, and EBNA1 Specific CTL, EBV-Positive Lymphoma [MABEL]).

Immune checkpoint therapy targeting the PD-1/PD-L1 axis has revolutionised the treatment of solid tumors. However, T cell exhaustion underpins resistance to current anti-PD-1 therapies, resulting in lower response rates in cancer patients. CD28 is a T cell costimulatory receptor that can influence the PD-1 signalling pathway (and vice versa). CD28 signalling has the potential to counter T cell exhaustion by serving as a potential complementary response to traditional anti-PD-1 therapies. Here we discuss the interplay between PD-1 and CD28 in T cell immunotherapy and additionally how CD28 transcriptionally modulates T cell exhaustion. We also consider clinical attempts at targeting CD28; the challenges faced by past attempts and recent promising developments.

Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, underscoring the need for improved cSCC prevention. Elimination of actinic keratosis (AK) precursor lesions is a major strategy to prevent cSCC. Topical calcipotriol and 5-fluorouracil (5-FU) have been shown to eliminate AKs and reduce the risk of cSCC development, but the mechanism was undefined. In this issue of the JCI, Oka et al. demonstrate that type 2 immunity is necessary and sufficient for the elimination of premalignant keratinocytes and cSCC prevention. Paired biopsies from AK lesions and unaffected skin revealed that only keratinocytes from AKs produced thymic stromal lymphopoietin (TSLP) and damage-associated molecular patterns, resulting in selective recruitment of Th2 cells to the AK lesion. In mouse models of skin carcinogenesis, TSLP was necessary to recruit Th2 cells and trigger IL-24-mediated keratinocyte cell death. These findings suggest that the TSLP/Th2/IL-24 axis is a potential therapeutic target for SCC prevention.

Metastatic disease is the final stage of breast cancer that accounts for vast majority of patient death. Mounting data over recent years strongly support the critical roles of the immune microenvironment in determining breast cancer metastasis. The latest single-cell studies provide further molecular evidence illustrating the heterogeneity of this immune microenvironment. This chapter summarizes major discoveries on the role of various immune cells in metastasis progression and discusses future research opportunities. Studies investigating immune heterogeneity within primary breast cancer and across different metastasis target organs can potentially lead to more precise treatment strategies with improved efficacy.

Tumor immunotherapy, modulating innate and adaptive immunity, has become an important therapeutic strategy. However, the tumor immune microenvironment's (TIME) complexity and heterogeneity challenge tumor immunotherapy. Hydrogel is a hydrophilic three-dimensional (3D) mesh structure with good biocompatibility and drug release control, which is widely used in drug delivery, agriculture, industry, etc. Hydrogels loaded with immune cells, cytokines, immune checkpoint inhibitors, and anti-tumor drugs can achieve targeted delivery and ultimately activate the immune response in the TIME. In this review, we will summarize the components of the TIME and their immune effects, the emerging immunomodulatory agents, the characteristics and functions of hydrogels, and how hydrogels regulate innate and adaptive immune cells in the TIME.

Total resection of glioblastoma (GB) tumors is nearly impossible, and systemic administration of temozolomide (TMZ) is often inadequate. This study presents a hybrid layered composite nanofiber mesh (LHN) designed for localized treatment in GB tumor bed. The LHN, consisting of polyvinyl alcohol and core-shell polylactic acid layers, was loaded with TMZ and rutin. In vitro analysis revealed that LHNTMZ and LHNrutin decelerated epithelial-mesenchymal transition and growth of stem-like cells, while the combination, LHNTMZ +rutin, significantly reduced sphere size compared to untreated and LHNTMZ-treated cells (P < 0.0001). In an orthotopic C6-induced GB rat model, LHNTMZ +rutin therapy demonstrated a more pronounced tumor-reducing effect than LHNTMZ alone. Tumor volume, assessed by magnetic resonance imaging, was significantly reduced in LHNTMZ +rutin-treated rats compared to untreated controls. Structural changes in tumor mitochondria, reduced membrane potential, and decreased PARP expression indicated the activation of apoptotic pathways in tumor cells, which was further confirmed by a reduction in PHH3, indicating decreased mitotic activity of tumor cells. Additionally, the local application of LHNs in the GB model mitigated aggressive tumor features without causing local tissue inflammation or adverse systemic effects. This was evidenced by a decrease in the angiogenesis marker CD31, the absence of inflammation or necrosis in H&E staining of the cerebellum, increased production of IFN-γ, decreased levels of interleukin-4 in splenic T cells, and lower serum AST levels. Our findings collectively indicate that LHNTMZ +rutin is a promising biocompatible model for the local treatment of GB.

T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.

To systematically present an overview of randomized controlled trials on transcutaneous electrical acupoint stimulation (TEAS) using bibliometric methods, and describe the role and mechanisms of TEAS in most prevalent diseases. Relevant literature was searched in China National Knowledge Infrastructure, Wanfang Data, VIP, SinoMed, PubMed, and Web of Science. The literature was imported and screened into NoteExpress, screened according to inclusion and exclusion criteria, and analyzed using Excel and CiteSpace 6.3R1 software. A total of 1296 documents were included. The number of publications increased annually after 2012. Junlu Wang was the most prolific author. The main research institutions were Peking University, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Shuguang Hospital, and Tongde Hospital of Zhejiang Province. The research hotspots in this field include perioperative care, cancer, pain management, and stroke, primarily focusing on analgesia, immune enhancement, antihypertension, and reduction of gastrointestinal disorders. The main regulatory mechanisms of TEAS include the control of inflammation, oxidative stress, and regulation of the autonomic nervous system. TEAS is most widely used in the elderly, with PC6, ST36, and LI4 being the most frequently studied acupoints in clinical randomized controlled trials. The concept of accelerated rehabilitation is gradually being applied to TEAS, representing an emerging trend for future development. Clinical research on TEAS is rapidly developing, with a focus on applications in cancer and perioperative care. Future research should expand collaboration and conduct high-level clinical and mechanistic studies, which will contribute to the development of standardized protocols and clinical practice.

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) immunotherapies have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas, but not all patients respond to treatment. To identify the set of EBV-directed antibody responses associated with clinical response in patients with EBV-associated lymphomas, we comprehensively characterized the immune response to the complete EBV proteome using a custom protein microarray in 56 EBV-associated lymphoma patients who were treated with EBVST infusions enrolled in Phase I clinical trials. Significant differences in antibody profiles between responders and non-responders emerged at 3 months post-EBVST infusion. Twenty-five IgG antibodies were present at significantly higher levels in non-responders compared to responders at 3 months post-EBVST infusion, and 10 of these IgG antibody associations remained after adjustment for sex, age, and cancer diagnosis type. Random forest prediction analysis further confirmed that these 10 antibodies were important for predicting clinical response. Differential IgG antibody responses were directed against LMP2A (four fragments), BGRF1/BDRF1 (two fragments), LMP1, BKRF2, BKRF4, and BALF5. Paired analyses using blood samples collected at both pre-infusion and 3 months post-EBVST infusion indicated an increase in the mean antibody level for six other anti-EBV antibodies (IgG: BGLF2, LF1, BGLF3; IgA: BGLF3, BALF2, BBLF2/3) in non-responders. Overall, our results indicate that EBV-directed antibodies can be biomarkers for predicting the clinical response of individuals with EBV-associated lymphomas treated with EBVST infusions.

Immunotherapy is one of the most promising therapeutic approaches in the field of cancer treatment. As a tumor progresses, tumor cells employ an array of immune-regulatory mechanisms to suppress immune responses within the tumor microenvironment. Using our understanding of these mechanisms, cancer immunotherapy has been developed to enhance the immune system's effectiveness in treating cancer. Numerous cancer immunotherapies are currently in clinical use, yet many others are either in different stages of development or undergoing clinical studies. In this paper, we briefly discuss the features and current status of cancer immunotherapies. This includes the application of monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapy, cytokine therapy, cancer vaccines, and gene therapy, all of which have gained significant recognition in clinical practice. Additionally, we discuss limitations that may hinder successful clinical utilization and promising strategies, such as combining immunotherapy with nanotechnology.

The prevalence of diseases characterised by eosinophilia is on the rise, emphasising the importance of understanding the role of eosinophils in these conditions. Eosinophils are a subset of granulocytes that contribute to the body's defence against bacterial, viral, and parasitic infections, but they are also implicated in haemostatic processes, including immunoregulation and allergic reactions. They contain cytoplasmic granules which can be selectively mobilised and secrete specific proteins, including chemokines, cytokines, enzymes, extracellular matrix, and growth factors. There are multiple biological and emerging functions of these specialised immune cells, including cancer surveillance, tissue remodelling and development. Several oral diseases, including oral cancer, are associated with either tissue or blood eosinophilia; however, their exact mechanism of action in the pathogenesis of these diseases remains unclear. This review presents a comprehensive synopsis of the most recent literature for both clinicians and scientists in relation to eosinophils and oral diseases and reveals a significant knowledge gap in this area of research.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-β (TGF-β) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Epstein-Barr virus (EBV) is a pathogen known to cause a number of malignancies, often taking years for them to develop after primary infection. EBV-associated gastric cancer (EBVaGC) is one such malignancy, and is an immunologically, molecularly and pathologically distinct entity from EBV-negative gastric cancer (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress a number of immune regulatory genes to help form an immunosuppressive tumor microenvironment (TME), have improved prognosis, and overall have an "immune-hot" phenotype. This review provides an overview of the histopathology, clinical features and clinical outcomes of EBVaGCs. We also summarize the differences between the TMEs of EBVaGCs and EBVnGCs, which includes significant differences in cell composition and immune infiltration. A list of available EBVaGC and EBVnGC gene expression datasets and computational tools are also provided within this review. Finally, an overview is provided of the various chemo- and immuno-therapeutics available in treating gastric cancers (GCs), with a focus on EBVaGCs.

Lung cancer makes up one-fourth of all cancer-related mortality with the highest mortality rate among all cancers. Despite recent scientific advancements in cancer therapeutics, the 5-year survival rate of lung adenocarcinoma (LUAD) cancer patients remains below 15 percent. It has been suggested that the high mortality rate of LUAD is linked to the acquisition of progenitor-like cells with stem-like characteristics that assist the whole tumor in regulating immune cell infiltration. To examine this hypothesis further, this study mined several databases to explore the presence of stemness-related genes and miRNAs in LUAD cancers. We examine their association with immune and accessory cell infiltration rates and patient survival. We found 3 stem cell-related genes, ORC1L, KIF20A, and DLGAP5, present in LUAD that also correlate with changes in immune infiltration rates and reduced patient survival rates. Additionally, the modulation in myeloid-derived suppressor cell (MDSC) infiltration and miRNA hsa-mir-1247-3p mediated targeting of tumor suppressor SLC24A4 and oncogenes RAB3B and HJURP appears to primarily regulate LUAD patient survival. Given these findings, hsa-mir-1247-3p and/or its associated gene targets may offer a promising avenue to enhance patient survivability.

Cancer stem cells (CSCs) are believed to be crucial in the initiation, progression, and recurrence of cancer. CSCs are also known to be more resistant to cancer treatments. However, the interaction between CSCs and the immune microenvironment is complex and not fully understood. In current study we used single cell RNA sequence (scRNA-Seq, public dataset) technology to identify the characteristic of CSCs. We found that the lung adenocarcinoma cancer stem population is highly inflammatory and remodels the tumor microenvironment by secreting inflammatory factors, specifically the acute phase protein serum amyloid A (SAA). Next, we developed an ex-vivo autologous patient-derived organoids (PDOs) and peripheral blood mononuclear cells (PBMCs) co-culture model to evaluate the immune biological impact of SAA. We found that SAA not only promotes chemoresistance by inducing cancer stem transformation, but also restricts anti-tumor immunity and promotes tumor fibrosis by driving type 2 immunity, and α-SAA neutralization antibody could restrict treatment resistant and tumor fibrosis. Mechanically, we found that the malignant phenotype induced by SAA is dependent on P2X7 receptor. Our data indicate that cancer stem cells secreted SAA have significant biological impact to promote treatment resistant and tumor fibrosis by driving cancer stemness transformation and type 2 immunity polarization via P2X7 receptor. Notably, α-SAA neutralization antibody shows therapeutic potential by restricting these malignant phenotypes.

Immunotherapy represents an innovative approach to cancer treatment, based on activating the body's own immune system to combat tumor cells. Among various immunotherapy strategies, dendritic cell vaccines hold a special place due to their ability to activate T-lymphocytes, key players in cellular immunity, and direct them to tumor cells. In this study, the influence of dendritic cells processed with tumor-derived vesicles on the viability of melanoma cells in vitro was investigated. Dendritic cells were loaded with tumor-derived vesicles, after which they were used to activate T-cells. The study demonstrated that such modified T-cells exhibit high activity against melanoma cells, leading to a decrease in their viability. Our analysis highlights the potential efficacy of this approach in developing immunotherapy against melanoma. These results provide new prospects for further research and the development of antitumor strategies based on the mechanisms of T-lymphocyte activation using tumor-derived vesicles.

Characterization of the oral microbiota profile through various studies has shown an association between the microbiome and oral cancer; however, stage-specific determinants of dynamic changes in microbial communities of oral cancer remain elusive. Additionally, the influence of the intratumoral microbiota on the intratumoral immune system remains largely unexplored. Therefore, this study aims to stratify microbial abundance in the early-onset and subsequent stages of oral cancer and analyze their influence on clinical-pathological and immunological features. The microbiome composition of tissue biopsy samples was identified using 16S rRNA amplicon sequencing, while intratumoral and systemic immune profiling was done with flow cytometry and immunohistochemistry-based analysis. The bacterial composition differed significantly among precancer, early cancer, and late cancer stages with the enrichment of genera Capnocytophaga, Fusobacterium, and Treponema in the cancer group, while Streptococcus and Rothia were enriched in the precancer group. Late cancer stages were significantly associated with Capnocytophaga with high predicting accuracy, while Fusobacterium was associated with early stages of cancer. A dense intermicrobial and microbiome-immune network was observed in the precancer group. At the cellular level, intratumoral immune cell infiltration of B cells and T cells (CD4+ and CD8+) was observed with enrichment of the effector memory phenotype. Naive and effector subsets of tumor-infiltrating lymphocytes (TILs) and related gene expression were found to be distinctly associated with bacterial communities; most importantly, highly abundant bacterial genera of the tumor microenvironment were either negatively correlated or not associated with the effector lymphocytes, which led to the conclusion that the tumor microenvironment favors an immunosuppressive and nonimmunogenic microbiota. IMPORTANCE The gut microbiome has been explored extensively for its importance in the modulation of systemic inflammation and immune response; in contrast, the intratumoral microbiome is less studied for its influence on immunity in cancer. Given the established correlation between intratumoral lymphocyte infiltration and patient survival in cases of solid tumors, it was pertinent to explore the extrinsic factor influencing immune cell infiltration in the tumor. Modulation of intratumoral microbiota could have a beneficial effect on the antitumor immune response. This study stratifies the microbial profile of oral squamous cell carcinoma starting from precancer to late-stage cancer and provides evidence for their immunomodulatory role in the tumor microenvironment. Our results suggest combining microbiome study with immunological signatures of tumors for their prognostic and diagnostic application.

In situ vaccination with immunostimulatory compounds is a demonstrated means to treat tumors preclinically. While these therapeutic effects have been attributed to the actions of T cells or innate immune activation, characterisation of the humoral immune response is seldom performed. This study aims to identify whether the injection of immunoadjuvants, Addavax (Adda) and cytosine-phosphorothioate-guanine oligodeoxynucleotide (CpG), intratumorally can influence the antibody response. Specifically, whether intratumoral injection of immunoadjuvants can alter the tumor-specific antibody target, titre and isotype. Following this, the study aimed to investigate whether serum obtained from in situ vaccinated mice could neutralise circulating tumor cells. Serum was obtained from mice bearing B16F10-OVA-Luc-GFP tumors treated with immunoadjuvants. Antibody targets' titre and isotype were assessed by indirect ELISA. The ability of serum to neutralise circulating cancer cells was evaluated in a B16F10 pseudo-metastatic model. It was observed that tumor-bearing mice mount a specific anti-tumor antibody response. Antibody titre and target were unaffected by in situ vaccination with immunoadjuvants; however, a higher amount of IgG2c was produced in mice receiving Adda plus CpG. Serum from in situ vaccinated mice was unable to neutralise circulating B16F10 cells. Thus, this study has demonstrated that anti-tumor antibody isotype may be modified using in situ vaccination; however, this alone is not sufficient to neutralise circulating cancer cells.

Cancer remains the second leading cause of death worldwide despite modern breakthroughs in medicine, and novel treatments are urgently needed. The revolutionary success of immune checkpoint inhibitors in the past decade serves as proof of concept that the immune system can be effectively harnessed to treat cancer. Cytokines are small signalling proteins with critical roles in orchestrating the immune response and have become an attractive target for immunotherapy. Type 1 immune cytokines, including interferon γ (IFNγ), interleukin-12 (IL-12), and tumour necrosis factor α (TNFα), have been shown to have largely tumour suppressive roles in part through orchestrating anti-tumour immune responses mediated by natural killer (NK) cells, CD8⁺ T cells and T helper 1 (Th1) cells. Conversely, type 2 immunity involving group 2 innate lymphoid cells (ILC2s) and Th2 cells are involved in tissue regeneration and wound repair and are traditionally thought to have pro-tumoural effects. However, it is found that the classical type 2 immune cytokines IL-4, IL-5, IL-9, and IL-13 may have conflicting roles in cancer. Similarly, type 2 immunity-related cytokines IL-25 and IL-33 with recently characterised roles in cancer may either promote or suppress tumorigenesis in a context-dependent manner. Furthermore, type 1 cytokines IFNγ and TNFα have also been found to have pro-tumoural effects under certain circumstances, further complicating the overall picture. Therefore, the dichotomy of type 1 and type 2 cytokines inhibiting and promoting tumours respectively is not concrete, and attempts of utilising these for cancer immunotherapy must take into account all available evidence. This review provides an overview summarising the current understanding of type 1 and type 2 cytokines in tumour immunity and discusses the prospects of harnessing these for immunotherapy in light of previous and ongoing clinical trials.

Cancer immunology and immunotherapy are driving forces of research and development in oncology, mostly focusing on CD8⁺ T cells and the tumor microenvironment. Recent progress highlights the importance of CD4⁺ T cells, corresponding to the long-known fact that CD4⁺ T cells are central players and coordinators of innate and antigen-specific immune responses. Moreover, they have now been recognized as anti-tumor effector cells in their own right. Here we review the current status of CD4⁺ T cells in cancer, which hold great promise for improving knowledge and therapies in cancer.

Historically, CD8⁺ T cells have been considered the most relevant effector cells involved in the immune response against tumors and have therefore been the focus of most cancer immunotherapy approaches. However, CD4⁺ T cells and their secreted factors also play a crucial role in the tumor microenvironment and can orchestrate both pro- and antitumoral immune responses. Depending on the cytokine milieu to which they are exposed, CD4⁺ T cells can differentiate into several phenotypically different subsets with very divergent effects on tumor progression. In this review, we provide an overview of the current knowledge about the role of the different T helper subsets in the immune system, with special emphasis on their implication in antitumoral immune responses. Furthermore, we also summarize therapeutic applications of each subset and its associated cytokines in the adoptive cell therapy of cancer.

Visceral obesity is a key risk factor in the development of oesophagogastric junctional adenocarcinoma (OGJ), predominantly via generation of systemic low grade inflammation. Obesity-induced inflammation promotes resistance to current standards of care, enhancing tumour cell growth and survival. This study investigates the effect of the visceral adipose tissue secretome from OGJ patients with early versus advanced tumours on T-cell immunity and the role of immune checkpoint blockade in enhancing anti-tumour immunity.

Visceral adipose conditioned media (ACM) from both early and late-stage OGJ patients significantly altered T cell activation status, upregulating co-stimulatory marker CD27 on T cells. ACM from both early and late-stage OGJ patients significantly altered immune checkpoint expression profiles downregulating immune checkpoints (ICs) on the surface of dual Th1/17-like and Th17-like cells and upregulating ICs on the surface of Th1-like cells and Treg cells. ACM derived from early-stage OGJ patients but not late-stage OGJ patients increased IFN-γ production by T cells. The addition of immune checkpoint blockers (ICBs) did not increase IFN-γ production by T cells in the presence of late-stage ACM, collectively highlighting the dichotomous immunostimulatory effect of early-stage ACM and immune-inhibitory effect of late-stage ACM. Interestingly, ACM from early-stage OGJ patients was more pro-inflammatory than ACM from late-stage patients, reflected by decreased levels of IL-17A/F, TNF-α, IL-1RA and IL-5.

The ACM-induced upregulation of ICs on T cells highlights a therapeutic vulnerability that could be exploited by ICBs to harness anti-cancer immunity and improve clinical outcomes for OGJ patients. Schematic workflow - (A) visceral adipose tissue was taken from OAC patients at time of surgery and cultured for 72 h in media. (B) The harvested ACM was co-cultured with healthy donor PBMCs that were concurrently activated with anti-CD3/28 for 48 h and T cell immunophenotyping was carried out by flow cytometry. Key findings - (A) Early and late stage ACM enhanced a Th1-like phenotype and upregulated CTLA-4 on Th1-like cells. A Th17-like phenotype was also enhanced in addition with a Treg-like phenotype. CTLA-4 and PD-L1 were upregulated on the surface of Treg-like cells. (B) ICB-attenuated IL-17 production by T cells. However, ACM attenuated ICB-mediated reduction in IL-10 production by T cells. Higher levels of pro-inflammatory factors were found in early stage ACM compared with late stage ACM.

The gastrointestinal tract is inhabited by trillions of commensal microorganisms that constitute the gut microbiota. As a main metabolic organ, the gut microbiota has co-evolved in a symbiotic relationship with its host, contributing to physiological homeostasis. Recent advances have provided mechanistic insights into the dual role of the gut microbiota in cancer pathogenesis. Particularly, compelling evidence indicates that the gut microbiota exerts regulatory effects on the host immune system to fight against cancer development. Some microbiota-derived metabolites have been suggested as potential activators of antitumor immunity. On the contrary, the disequilibrium of intestinal microbial communities, a condition termed dysbiosis, can induce cancer development. The altered gut microbiota reprograms the hostile tumor microenvironment (TME), thus allowing cancer cells to avoid immunosurvelliance. Furthermore, the gut microbiota has been associated with the effects and complications of cancer therapy given its prominent immunoregulatory properties. Therapeutic measures that aim to manipulate the interplay between the gut microbiota and tumor immunity may bring new breakthroughs in cancer treatment. Herein, we provide a comprehensive update on the evidence for the implication of the gut microbiota in immune-oncology and discuss the fundamental mechanisms underlying the influence of intestinal microbial communities on systemic cancer therapy, in order to provide important clues toward improving treatment outcomes in cancer patients.

Mast cell tumor (MCT) is the most common malignant skin tumor in dogs. In order to gain more information on the prognostic markers in MCT, the role of the eosinophil granulocytes infiltrates was investigated and assessed by the evaluation of tumor-associated tissue eosinophilia (TATE) in 87 canine cutaneous MCTs. In human medicine, high TATE are often described in highly angiogenic tumors: we therefore assessed the vascular endothelial growth factor (VEGF) expression in neoplastic mast cells. TATE and VEGF expression were compared between themselves, with histological grading, immunohistochemical expression of KIT and Ki-67, and with the recurrence. We found a statistically significant correlation between TATE and Patnaik grading (p = 0.041), Kiupel grading (p = 0.022), immunohistochemical KIT expression (p = 0.015), and tumor recurrence (p = 0.000). No associations were observed with Ki-67 and VEGF expression. This is the first evaluation of TATE and its prognostic value in canine MCTs in veterinary oncology. This study suggest that this investigation could be an important source of information for this tumor and for other neoplasms.

Despite advances in treating high-risk neuroblastoma, 50-60% of patients still suffer relapse, necessitating new treatment options. Bispecific trifunctional antibodies (trAbs) are a promising new class of immunotherapy. TrAbs are heterodimeric IgG-like molecules that bind CD3 and a tumor-associated antigen simultaneously, whereby inducing a TCR-independent anti-cancer T cell response. Moreover, via their functional Fc region they recruit and activate cells of the innate immune system like antigen-presenting cells potentially enhancing induction of adaptive tumor-specific immune responses.

We used the SUREK trAb, which is bispecific for GD2 and murine Cd3. Tumor-blind trAb and the monoclonal ch14.18 antibody were used as controls. A co-culture model of murine dendritic cells (DCs), T cells and a neuroblastoma cell line was established to evaluate the cytotoxic effect and the T cell effector function in vitro. Expression of immune checkpoint molecules on tumor-infiltrating T cells and the induction of an anti-neuroblastoma immune response using a combination of whole cell vaccination and trAb therapy was investigated in a syngeneic immunocompetent neuroblastoma mouse model (NXS2 in A/J background). Finally, vaccinated mice were assessed for the presence of neuroblastoma-directed antibodies. We show that SUREK trAb-mediated effective killing of NXS2 cells in vitro was strictly dependent on the combined presence of DCs and T cells.

Using a syngeneic neuroblastoma mouse model, we showed that vaccination with irradiated tumor cells combined with SUREK trAb treatment significantly prolonged survival of tumor challenged mice and partially prevent tumor outgrowth compared to tumor vaccination alone. Treatment led to upregulation of programmed cell death protein 1 (Pd-1) on tumor infiltrating T cells and combination with anti-Pd-1 checkpoint inhibition enhanced the NXS2-directed humoral immune response.

Here, we provide first preclinical evidence that a tumor vaccination combined with SUREK trAb therapy induces an endogenous anti-neuroblastoma immune response reducing tumor recurrence. Furthermore, a combination with anti-Pd-1 immune checkpoint blockade might even further improve this promising immunotherapeutic concept in order to prevent relapse in high-risk neuroblastoma patients.

Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with 10% of all gastric cancers (GCs) and 1.5% of all human cancers. EBV-associated GCs (EBVaGCs) are pathologically and clinically distinct entities from EBV-negative GCs (EBVnGCs), with EBVaGCs exhibiting differential molecular pathology, treatment response, and patient prognosis. However, the tumor immune landscape of EBVaGC has not been well explored. In this study, a systemic and comprehensive analysis of gene expression and immune landscape features was performed for both EBVaGC and EBVnGC. EBVaGCs exhibited many aspects of a T cell-inflamed phenotype, with greater T and NK cell infiltration, increased expression of immune checkpoint markers (BTLA, CD96, CTLA4, LAG3, PD1, TIGIT, and TIM3), and multiple T cell effector molecules in comparison with EBVnGCs. EBVaGCs also displayed a higher expression of anti-tumor immunity factors (PDL1, CD155, CEACAM1, galectin-9, and IDO1). Six EBV-encoded miRNAs (miR-BARTs 8-3p, 9-5p, 10-3p, 22, 5-5p, and 14-3p) were strongly negatively correlated with the expression of immune checkpoint receptors and multiple markers of anti-tumor immunity. These profound differences in the tumor immune landscape between EBVaGCs and EBVnGCs may help explain some of the observed differences in pathological and clinical outcomes, with an EBV-positive status possibly being a potential biomarker for the application of immunotherapy in GC.

The adaptive arm of the immune system is crucial for appropriate antitumor immune responses. It is generally accepted that clusters of differentiation 4+ (CD4+) T cells, which mediate T helper (Th) 1 immunity (type 1 immunity), are the primary Th cell subtype associated with tumor elimination. In this review, we discuss evidence showing that antitumor immunity and better prognosis can be associated with distinct Th cell subtypes in experimental mouse models and humans, with a focus on Th2 cells. The aim of this review is to provide an overview and understanding of the mechanisms associated with different tumor outcomes in the face of immune responses by focusing on the (1) site of tumor development, (2) tumor properties (i. e., tumor metabolism and cytokine receptor expression), and (3) type of immune response that the tumor initially escaped. Therefore, we discuss how low-tolerance organs, such as lungs and brains, might benefit from a less tissue-destructive immune response mediated by Th2 cells. In addition, Th2 cells antitumor effects can be independent of CD8+ T cells, which would circumvent some of the immune escape mechanisms that tumor cells possess, like low expression of major histocompatibility-I (MHC-I). Finally, this review aims to stimulate further studies on the role of Th2 cells in antitumor immunity and briefly discusses emerging treatment options.

Immunotherapy of gastrointestinal cancers is challenging; however, several lines of evidence suggest that adoptive transfer of stimulated or modified immune cells support not only protective role of immune cells in tumor microenvironment, but actively participate in the elimination of cancer cells.

In vivo studies employing cancer cell-derived allograft murine models of gastrointestinal cancers were performed. The effects of T helper (Th) 2 cells on gastrointestinal cancers growth and tumor microenvironment composition using adoptive transfer of Th2 cells, interleukin (IL)-5 treatment, and immunofluorescence, multiplex and real-time PCR were explored.

Here, we show that Th2 cells play an essential role in the inhibition of colon and pancreas cancers progression. In murine models of gastrointestinal tumors using adoptive transfer of Th2 cells, we identify that Th2 cells are responsible for generation of apoptotic factors and affect macrophage as well as eosinophil recruitment into tumors where they produce cytotoxic factors. Moreover, we found that Th2 cells lead to IL-5 hypersecretion, which links the anti-tumorigenic function of Th2 cells and eosinophils. Importantly, we noted that recombinant IL-5 administration is also related with inhibition of gastrointestinal tumor growth. Finally, using an in vitro approach, we documented that both Th2 cells and eosinophils are directly responsible for gastrointestinal cancer cell killing.

These data demonstrate the significance of Th2 cells, eosinophils and IL-5 in the inhibition of gastrointestinal tumor growth, and pointed toward tumor microenvironment reprogramming as a Th2 cell-mediated anti-tumorigenic mechanism of action.

In this review, we will summarize the effects of these perioperative anesthetics and anesthetic interventions on the immune system and tumorigenesis as well as address the related clinical evidence on cancer-related mortality and recurrence.

Cancer remains a leading cause of morbidity and mortality worldwide. For many solid tumors, surgery is one of the major therapies. Unfortunately, surgery promotes angiogenesis, shedding of circulating cancer cells, and suppresses immunity. Hence, the perioperative period has a close relationship with cancer metastases or recurrence. In the perioperative period, patients require multiple anesthetic management including anesthetics, anesthetic techniques, and body temperature control. Preclinical and retrospective studies have found that these anesthetic agents and interventions have complex effects on cancer outcomes. Therefore, well-planned, prospective, randomized controlled trials are required to explore the effects of different anesthetics and techniques on long-term outcomes after cancer surgery. Due to the conflicting effects of anesthetic management on cancer recurrence, further preclinical and clinical trials are required and beneficial to the development of systemic cancer therapies.

Excision repair cross-complementation group 6 like (ERCC6L), a polo-like kinase 1 (PLK1)-interacting checkpoint helicase, confers a high risk of cancer and enhances the progression of a variety of cancers. The present investigation aimed to elucidate the pan-cancer expression patterns of ERCC6L and to examine the possibility of using this gene for patient diagnosis and prognosis.

The expression patterns of ERCC6L in normal and cancer patients at various clinical stages were explored based on TCGA datasets. Subsequently, Bioinformatics techniques were then used to analyze patient's survival probabilities, Cox multivariate clinical parameters, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms related to ERCC6L, the correlation between mRNA expression levels and patient survival, genetic alterations or somatic mutations of ERCC6L, and immune infiltration.

Most cancer types had higher ERCC6L mRNA levels than normal tissue. Higher ERCC6L expression levels were correlated with poor prognosis for cancer patients. Thus, ERCC6L may serve as an effective diagnostic and prognostic marker for multiple cancers. Moreover, ERCC6L expression levels were higher in patients with higher clinical tumor grades and were associated with poor prognoses at these stages. GO and KEGG analyses revealed a correlation between ERCC6L expression levels and chromatin and cell cycle events. We also found that the mRNA expression level of the ERCC6L promoter and a favorable prognosis was negatively correlated with the promoter's methylation but not with copy number variation. A quantitative analysis of immune infiltration suggested a positive correlation between ERCC6L levels and the infiltration of Th2 immune cells in main cancer types. Finally, we examined the ERCC6L somatic mutations, especially single-nucleotide variants, and ERCC6L expression-related drug sensitivity.

Herein, we reported a comprehensive investigation of the tumor-promoting role of ERCC6L in various cancer types. ERCC6L is a candidate biomarker for diagnosing and unfavorable prognosis of specific cancers.

Treg cells acquire distinct transcriptional properties to suppress specific inflammatory responses. Transcription characteristics of Treg cells are regulated by epigenetic modifications, the mechanism of which remains obscure. Here, we report that Setd2, a histone H3K36 methyltransferase, is important for the survival and suppressive function of Treg cells, especially those from the intestine. Setd2 supports GATA3⁺ST2⁺ intestinal thymic-derived Treg (tTreg) cells by facilitating the expression and reciprocal relationship of GATA3 and ST2 in tTreg cells. IL-33 preferentially boosts Th2 cells rather than GATA3⁺ Treg cells in Foxp3^Cre-YFPSetd2 ^flox/flox mice, corroborating the constraint of Th2 responses by Setd2 expression in Treg cells. SETD2 sustains GATA3 expression in human Treg cells, and SETD2 expression is increased in Treg cells from human colorectal cancer tissues. Epigenetically, Setd2 regulates the transcription of target genes (including Il1rl1) by modulating the activity of promoters and intragenic enhancers where H3K36me3 is typically deposited. Our findings provide mechanistic insights into the regulation of Treg cells and intestinal immunity by Setd2.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The development of biomarkers for early detection and monitoring of HCC has not shown significant progress. Meanwhile, the second adenomatous polyposis-related gene, MUTYH, which encodes a DNA glycosylase, has been observed in its contribution to oxidative DNA damage repair. Abnormal expression of MUTYH can reduce cell survival rate. Therefore, this study investigated the usefulness of MUTYH in diagnosing and prognosis HCC.

Using The Cancer Genome Atlas (TCGA) data, we analyzed the prognostic value of MUTYH in HCC. We used logistic regression, Wilcoxon signed-rank test, and Kruskal-Wallis test to examine MUTYH expression concerning clinical-pathologic characteristics. Univariate and multivariate Cox regression methods and Kaplan-Meier analysis were applied to determine the related prognostic factors of HCC. The enrichment analysis (GSEA) was used to determine the critical pathways associated with MUTYH. The single-sample gene set enrichment analysis (ssGSEA) was conducted to examine the correlation between MUTYH expression and cancer immune infiltration.

The higher expression of MUTYH in HCC patients was associated with a poorer overall survival rate and a shorter disease-specific survival rate. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that all differentially expressed genes (DEGs) between the high and low expression levels of MUTYH significantly enriched in the trace ligand-receptor interaction, cell cycle, oocyte meiosis, gap junction, and DNA replication. Group analysis revealed the signals of their open access. The neuron system, M phase, DNA repair, Rho GTPase effector, and cell cycle checkpoints were significantly enriched. ssGSEA showed a positive correlation between MUTYH expression and the infiltration levels of Th2 cells, NK cells, and T helper cells. Moreover, a negative correlation was found between MUTYH expression and the infiltration levels of dendritic cells (DCs) and cytotoxic cells.

MUTYH expression levels were positively correlated with immune checkpoint gene expression levels in HCC tissues. The expression level of MUTYH was related to the prognosis of HCC and the immune infiltration of HCC.

Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity = 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR = 1.17, 95% CI: 1.04, 1.31; P for heterogeneity = 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers.

Multiple preclinical studies have shown improved outcomes when radiation therapy is combined with immune modulating antibodies. However, to date, many of these promising results have failed to translate to successful clinical studies. This led us to explore additional checkpoint and co-stimulatory pathways that may be regulated by radiation therapy. Here, we demonstrate that radiation increases the expression of inducible T cell co-stimulator (ICOS) on both CD4 and CD8 T cells in the blood following treatment. Moreover, when we combined a novel ICOS agonist antibody with radiation we observed durable cures across multiple tumor models and mouse strains. Depletion studies revealed that CD8 T cells were ultimately required for treatment efficacy, but CD4 T cells and NK cells also partially contributed to tumor control. Phenotypic analysis showed that the combination therapy diminished the increased infiltration of regulatory T cells into the tumor that typically occurs following radiation alone. Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models.

Despite the dynamic development of cancer research, annually millions of people die of cancer. The human immune system is the major 'guard' against tumor development. Unfortunately, cancer cells have the ability to evade the immune system and continue to grow. The proper understanding of the intricate immune response in tumorigenesis remains the holy grail of cancer immunology and designing effective immunotherapy. To decode the immune responses in cancer, in recent years, proteomics studies have received considerable attention. Proteomics studies focus on the detection and quantification of proteins, which are the effectors of biological functions, and as such, are proven to reflect the cell state more accurately, in comparison to genomic or transcriptomic studies. In this review, we discuss the proteomics studies applied to characterize the immune responses in cancer and tumor immune microenvironment heterogeneity. Further, we describe emerging single-cell proteomics approaches that have the potential to be applied in cancer immunity studies.

Our body is constantly exposed to pathogens or external threats, but with the immune response that our body can develop, we can fight off and defeat possible attacks or infections. Nevertheless, sometimes this threat comes from an internal factor. Situations such as the existence of a tumour also cause our immune system (IS) to be put on alert. Indeed, the link between immunology and cancer is evident these days, with IS being used as one of the important targets for treating cancer. Our IS is able to eliminate those abnormal or damaged cells found in our body, preventing the uncontrolled proliferation of tumour cells that can lead to cancer. However, in several cases, tumour cells can escape from the IS. It has been observed that immune cells, the extracellular matrix, blood vessels, fat cells and various molecules could support tumour growth and development. Thus, the developing tumour receives structural support, irrigation and energy, among other resources, making its survival and progression possible. All these components that accompany and help the tumour to survive and to grow are called the tumour microenvironment (TME). Given the importance of its presence in the tumour development process, this review will focus on one of the components of the TME: immune cells. Immune cells can support anti-tumour immune response protecting us against tumour cells; nevertheless, they can also behave as pro-tumoural cells, thus promoting tumour progression and survival. In this review, the anti-tumour and pro-tumour immunity of several immune cells will be discussed. In addition, the TME influence on this dual effect will be also analysed.