The implication of pyroptosis in cancer immunology:Current advances and prospects

Pyroptosis is a regulated cell death pathway involved in numerous human diseases,especially malignant tumors.Recent studies have identified multiple pyroptosis-associated signaling molecules,like caspases,gasdermin family and inflammasomes.In addition,increasing in vitro and in vivo studies have shown the significant linkage between pyroptosis and immune regulation of cancers.Pyroptosis-associated biomarkers regulate the infiltration of tumor immune cells,such as CD4^(+) and CD8^(+) T cells,thus strengthening the sensitivity to therapeutic strategies.In this review,we explained the relationship between pyroptosis and cancer immunology and focused on the significance of pyroptosis in immune regulation.We also proposed the future application of pyroptosis-associated biomarkers in basic research and clinical practices to address malignant behaviors.Exploration of the underlying mechanisms and biological functions of pyroptosis is critical for immune response and cancer immunotherapy.

Review:On dendritic cell-based therapy for cancers

Dendritic cells (DCs), the most prevalent antigen-presenting cell in vivo, had been widely characterized in the last three decades. DCs are present in almost all tissues of the body and play cardinal roles in recognition of microbial agents,autoantigens, allergens and alloantigen. DCs process the microbial agents or their antigens and migrate to lymphoid tissues to present the antigenic peptide to lymphocytes. This leads to activation of antigen-specific lymphocytes. Initially, it was assumed that DCs are principally involved in the induction and maintenance of adaptive immune responses, but now it is evident that DCs also have important roles in innate immunity. These features make DCs very good candidates for therapy against various pathological conditions including malignancies. Initially, DC-based therapy was used in animal models of cancers. Data from these studies inspired considerable optimism and DC-based therapies was started in human cancers 8 years ago. In general,DC-based therapy has been found to be safe in patients with cancers, although few controlled trials have been conducted in this regard. Because the fundamentals principles of human cancers and animal models of cancers are different, the therapeutic efficacy of the ongoing regime of DC-based therapy in cancer patients is not satisfactory. In this review, we covered the various aspects that should be considered for developing better regime of DC-based therapy for human cancers.

B cells in pancreatic cancer stroma

Pancreatic cancer is a disease with high unmet clinical need.Pancreatic cancer is also characterised by an intense fibrotic stroma,which harbours many immune cells.Studies in both human and animal models have demonstrated that the immune system plays a crucial role in modulating tumour onset and progression.In human pancreatic ductal adenocarcinoma,high B-cell infiltration correlates with better patient survival.Hence,B cells have received recent interest in pancreatic cancer as potential therapeutic targets.However,the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to study.Nevertheless,it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells(DCs),surrounded by T cells and DCs to form tertiary lymphoid structures(TLS).TLS are increasingly recognised as sites for antigen presentation,T-cell activation,Bcell maturation and differentiation in plasma cells.In this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.

Synthetic and immunological studies on the OCT4 immunodominant motif antigen-based anti-cancer vaccine

Objective:Cancer stem cell is one of the important causes of tumorigenesis as well as a drug target in the treatment of malignant tumor.However,at present,there is no immune vaccine targeting these cells.Octamer-binding transcription factor 4(OCT4),a marker of embryonic stem cells and germ cells,often highly expresses in the early stages of tumorigenesis and is therefore a good candidate for cancer vaccine development.Methods:To identify the optimal carrier and adjuvant combination,we chemically synthesized and linked three different OCT4 epitope antigens to a carrier protein,keyhole limpet hemocyanin(KLH),combined with Toll-like receptor 9 agonist(TLR9).Results:Immunization with OCT4-3+TLR9 produced the strongest immune response in mice.In prevention assays,significant tumor growth inhibition was achieved in BABL/c mice treated with OCT4-3+TLR9(P<0.01).Importantly,the results showed that cytotoxic T lymphocyte activity and the inhibition of tumor growth were enhanced in mice immunized with OCT4-3 combined with TLR9.Meanwhile,multiple cytokines[such as interferon(IFN)-γ(P<0.05),interleukin(IL)-12(P<0.05),IL-2(P<0.01),and IL-6(P<0.05)]promoting cellular immune responses were shown to be greatly enhanced in mice immunized with OCT4-3+TLR9.Moreover,we considered safety considerations in terms of the composition of the vaccines to help facilitate the development of effective next-generation vaccines.Conclusions:Collectively,these experiments demonstrated that combination therapy with TLR9 agonist induced a tumor-specific adaptive immune response,leading to the suppression of primary tumor growth in testis embryonic carcinoma.

SC及NDV修饰的瘤苗治疗胃癌的实验疗效研究

目的 :研究中药三棱、莪术的提取物SC修饰构建的肿瘤细胞疫苗对SGC 790 1胃癌细胞株的抗瘤效应及联合新城鸡疫病毒疫苗的实验杀瘤疗效。方法 :对SGC 790 1胃肿瘤细胞进行系列处理 ,用SC(sparganiumstoloniferumBuehhum、Curcumazedoariarosc SC ,Chinesetraditionalmedicine )及NDV (新城鸡瘟病毒 )对其进行生物构建 ,修饰构建的瘤苗经免疫小鼠 (1次 /周× 4 ) 2 8d后 ,接种SGC 790 1胃肿瘤细胞 ,观察抑制肿瘤肺转移、皮下结节形成及生存时间状况。结果 :经SC修饰构建的SC SGC 790 1瘤苗能明显阻止胃癌细胞的肺转移 ,显著抑制皮下肿瘤结节形成 ,能明显延长荷瘤鼠的生存时间 ,与对照组相比差异有显著性 (P <0 0 5 )。由NDV构建的疫苗的抗瘤作用低于SC瘤苗组 ,在延长荷瘤鼠生存期方面和单瘤苗组相近 ,SC与NDV联合构建的瘤苗其抗瘤未呈生物放大及相加效应。结论 :SC修饰构建的SGC 790 1新型疫苗可以增强胃肿瘤细胞的免疫原性 。

Cancer metabolism and tumor microenvironment:fostering each other?

The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live.Metabolic reprogramming supports tumor cells’high demand of biogenesis for their rapid proliferation,and helps tumor cells to survive under certain genetic or environmental stresses.Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes,in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways.Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation.This cancer metabolic phenotype,described firstly by German physiologist Otto Warburg,ensures enhanced glycolytic metabolism for the biosynthesis of macromolecules.The conception of metabolite signaling,i.e.,metabolites are regulators of cell signaling,provides novel insights into how reactive oxygen species(ROS)and other metabolites deregulation may regulate redox homeostasis,epigenetics,and proliferation of cancer cells.Moreover,the unveiling of noncanonical functions of metabolic enzymes,such as the moonlighting functions of phosphoglycerate kinase 1(PGK1),reassures the importance of metabolism in cancer development.The metabolic,microRNAs,and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome.Among them,cancer microenvironmental cells are immune cells which exert profound effects on cancer cells.Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.

Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febrile or infectious episode.Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon,and it is recognized that immunosuppression is associated with a higher cancer risk.The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment.Effective immunity against cancer involves complex interactions between the tumor,the host,and the environment.Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer,since attention has become more focused on the“biologic passport”of the individual tumor rather than the site of origin of the tumor.The different types of cancer immunotherapies discussed here include biologic modifiers,such as cytokines and vaccines,adoptive cell therapies,oncolytic viruses,and antibodies against immune checkpoint inhibitors,such as the co-inhibitory T-cell receptor PD-1 and one of its ligands,programmed death-ligand 1.

The Immunome of Colon Cancer: Functional In Silico Analysis of Antigenic Proteins Deduced from IgG Microarray Pro?ling

Characterization of the colon cancer immunome and its autoantibody signature from differentially-reactive antigens （DIRAGs） could provide insights into aberrant cellular mechanisms or enriched networks associated with diseases. The purpose of this study was to characterize the antibody profile of plasma samples from 32 colorectal cancer （CRC） patients and 32 controls using proteins isolated from 15,417 human cDNA expression clones on microarrays. 671 unique DIRAGs were identified and 632 were more highly reactive in CRC samples. Bioinformatics analyses reveal that compared to control samples, the immunoproteomic IgG profiling of CRC samples is mainly associated with cell death, survival, and proliferation pathways, especially proteins involved in EIF2and mTOR signaling. Ribosomal proteins （e.g., RPL7, RPL22, and RPL27A） and CRC-related genes such as APC, AXIN1, E2F4, MSH2, PMS2, and TP53 were highly enriched. In addition, dif- ferential pathways were observed between the CRC and control samples. Furthermore, 103 DIR- AGs were reported in the SEREX antigen database, demonstrating our ability to identify known and new reactive antigens. We also found an overlap of 7 antigens with 48 ＂CRC genes.＂ These data indicate that immunomies profiling on protein mieroarrays is able to reveal the complexity of immune responses in cancerous diseases and faithfully reflects the underlying pathology.

Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation

Cytotoxic T cells targeting cancer neoantigens harboring driver mutations can lead to durable tumor regression in an HLAIdependent manner.However,it is difficult to extend the population of patients who are eligible for neoantigen-based immunotherapy,as immunogenic neoantigen-HLA pairs are rarely shared across different patients.Thus,a way to find other human leukocyte antigen(HLA)alleles that can also present a clinically effective neoantigen is needed.Recently,neoantigen-based immunotherapy targeting the KRAS G12D mutation in patients with HLA-C*08:02 has shown effectiveness.In a proof-ofconcept study,we proposed a combinatorial strategy(the combination of phylogenetic and structural analyses)to find potential HLA alleles that could also present KRAS G12D neoantigen.Compared to in silico binding prediction,this strategy avoids the uneven accuracy across different HLA alleles.Our findings extend the population of patients who are potentially eligible for immunotherapy targeting the KRAS G12D mutation.Additionally,we provide an alternative way to predict neoantigen-HLA pairs,which maximizes the clinical usage of shared neoantigens.

IL-33 drives the antitumor effects of dendritic cells via the induction of Tc9 cells

Dendritic cell(DC)tumor vaccines exert their antitumor effects through the induction of effector T cells.We recently identified Tc9 cells as a new potent antitumor effector T cell subset.However,approaches to direct DCs to preferably prime antitumor Tc9 cells should be further exploited.Here,we demonstrate that the addition of interleukin(IL)-33 potently promotes the induction of Tc9 cells by DCs in vitro and in vivo.IL-33 treatment also drives the cytotoxic activities of DC-induced Tc9 cells.Notably,IL-33 treatment enhances cell survival and proliferation of DC-primed CD8+T cells.More importantly,the addition of IL-33 during in vitro priming of tumor-specific Tc9 cells by DCs increases the antitumor capability of Tc9 cells.Mechanistic studies demonstrated that IL-33 treatment inhibits exhaustive CD8+T cell differentiation by inhibiting PD-1 and 2B4 expression and increasing IL-2 and CD127(IL-7 receptor-α,IL-7Rα)expression in CD8+T cells.Finally,the addition of IL-33 further promotes the therapeutic efficacy of DC-based tumor vaccines in the OT-I mouse model.Our study demonstrates the important role of IL-33 in DC-induced Tc9 cell differentiation and antitumor immunity and may have important clinical implications.

RNA2Immune:A Database of Experimentally Supported Data Linking Non-coding RNA Regulation to The Immune System

Non-coding RNAs(ncRNAs),such as microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as important regulators of the immune system and are involved in the control of immune cell biology,disease pathogenesis,as well as vaccine responses.A repository of ncRNA-immune associations will facilitate our understanding of ncRNA-dependent mechanisms in the immune system and advance the development of therapeutics and prevention for immune disorders.Here,we describe a comprehensive database,RNA2Immune,which aims to provide a high-quality resource of experimentally supported database linking ncRNA regulatory mechanisms to immune cell function,immune disease,cancer immunology,and vaccines.The current version of RNA2Immune documents 50,433 immune-ncRNA associations in 42 host species,including(1)6690 ncRNA associations with immune functions involving 31 immune cell types;(2)38,672 ncRNA associations with 348 immune diseases;(3)4833 ncRNA associations with cancer immunology;and(4)238 ncRNA associations with vaccine responses involving 26 vaccine types targeting 22 diseases.RNA2Immune provides a user-friendly interface for browsing,searching,and downloading ncRNA-immune system associations.Collectively,RNA2Immune provides important information about how ncRNAs influence immune cell function,how dysregulation of these ncRNAs leads to pathological consequences(immune diseases and cancers),and how ncRNAs affect immune responses to vaccines.

A tumor-associated heparan sulfate-related glycosaminoglycan promotes the generation of functional regulatory T cells

Functional Tregs play a key role in tumor development and progression,representing a major barrier to anticancer immunity.The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood.Herein,by using NMR,chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses,we demonstrate that the tumoral carbohydrate A10(Ca10),a cell-surface carbohydrate derived from Ehrlich’s tumor(ET)cells,is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs.Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming,PD-L1,IL-10,and IDO.Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features.In solid ET-bearing mice,we found positive correlations between Ca10 serum levels,tumor size and splenic Treg numbers.Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice.Remarkably,we provide evidence supporting the presence of a circulating human Ca10 counterpart(Ca10H)and show,for the first time,that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals.Of note,these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases.Collectively,we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer.The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.