• Cancer
• Immunomodulation
• Immunotherapy
• Nanovaccines
• Vaccines

• Humans
• Cancer Vaccines/immunology
• Animals
• Neoplasms/immunology
• Neoplasms/therapy
• Nanoparticles/chemistry
• Immunotherapy/methods
• Tumor Microenvironment/immunology
• Nanotechnology/methods
• Nanovaccines

• Brain cancer
• Brain tumor
• Clinical trials
• Glioblastoma
• Personalized medicine
• mRNA vaccine

• Glioblastoma/therapy
• Humans
• Brain Neoplasms/therapy
• Cancer Vaccines/therapeutic use
• Precision Medicine/methods
• mRNA Vaccines
• RNA, Messenger/genetics
• RNA, Messenger/therapeutic use
• Immunotherapy/methods
• Clinical Trials as Topic
• Animals
• Temozolomide/therapeutic use

• Cancer
• Immunotherapy
• Membrane vesicle
• Nanocarrier
• Nanovaccine
• Tumor vaccine

• Humans
• Cancer Vaccines
• Nanovaccines
• Neoplasms/therapy
• Immunotherapy
• Antigens, Neoplasm
• Nanoparticles/chemistry

In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of various tumors, greatly improving clinical efficacy. As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery, chemotherapy, radiotherapy and targeted therapy, the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells, features that are also important when distinguishing malignant tumors from “cold tumors” or “hot tumors”. At present, only a small proportion of colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) or who are microsatellite instability-high (MSI-H) can benefit from ICI treatments because these patients have the characteristics of a “hot tumor”, with a high tumor mutational burden (TMB) and massive immune cell infiltration, making the tumor more easily recognized by the immune system. In contrast, a majority of CRC patients with proficient MMR (pMMR) or who are microsatellite stable (MSS) have a low TMB, lack immune cell infiltration, and have almost no response to immune monotherapy; thus, these tumors are “cold”. The greatest challenge today is how to improve the immunotherapy response of “cold tumor” patients. With the development of clinical research, immunotherapies combined with other treatment strategies (such as targeted therapy, chemotherapy, and radiotherapy) have now become potentially effective clinical strategies and research hotspots. Therefore, the question of how to promote the transformation of “cold tumors” to “hot tumors” and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration. Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.

• Colorectal cancer
• Immune checkpoint inhibitors
• Cold tumors
• Immunotherapy mechanism
• Combination therapy
• Effector T cells

• Allergy
• Autoimmunity
• Cancer
• Database
• Epitope
• Infectious disease
• Transplant

• Humans
• Epitopes
• Siblings
• Databases, Factual
• Antigens
• Neoplasms
• Databases, Protein

• 75N93019C00001 NIAID NIH HHS
• U24 CA248138 NCI NIH HHS

• Bone metastasis
• Cancer
• Chemokines
• Drug resistance
• Tumor heterogeneity

• Male
• Humans
• Chemokines/metabolism
• Receptors, Chemokine/metabolism
• Bone Neoplasms/genetics
• Bone Neoplasms/secondary
• Cell Transformation, Neoplastic
• Tumor Microenvironment/genetics

• U01 CA185148 NCI NIH HHS

• Aptamer
• Drug delivery
• Surface modification

• Aptamers, Nucleotide
• Drug Delivery Systems/methods
• Drug Liberation
• Excipients
• Humans
• Male
• Nanoparticles
• Neoplasms/drug therapy
• Polyethylene Glycols/chemistry
• Polymers

• cancer therapy
• immunotherapy
• nanovaccines

• LGF21H160004 to XLF, and LGF22H160046 to HRL Zhejiang Provincial Science and Technology Projects
• 2021-3-040 to KTJ, and 2021-3-046 to HRL Jinhua Municipal Science and Technology Projects

Cancer immunotherapy is a revolutionary type of cancer therapy. It uses the patient’s own immune system to fight and potentially cure cancer. The first major breakthrough of immunotherapy came from successful clinical trials for melanoma treatments. Since then, researchers have focused on understanding the science behind immunotherapy, so that patients with other types of cancer may also benefit. One of the major findings is that the T cells in melanoma patients may recognize a specific type of tumor antigen, called neoantigens, and then kill tumor cells that present these neoantigens. The neoantigens mainly arise from the DNA mutations found in tumor cells. These mutations are translated into mutated proteins that are then distinguished by T cells. In this article, we discuss the critical role of T cells in immunotherapy, as well as the clinical trials that shaped the treatments for melanoma.

Patients with metastatic cutaneous melanoma have experienced significant clinical responses after checkpoint blockade immunotherapy or adoptive cell therapy. Neoantigens are mutated proteins that arise from tumor-specific mutations. It is hypothesized that the neoantigen recognition by T cells is the critical step for T-cell-mediated anti-tumor responses and subsequent tumor regressions. In addition to describing neoantigens, we review the sentinel and ongoing clinical trials that are helping to shape the current treatments for patients with cutaneous melanoma. We also present the existing evidence that establishes the correlations between neoantigen-reactive T cells and clinical responses in melanoma immunotherapy.

• T cell
• immunotherapy
• melanoma
• neoantigen

• UL1 TR003107 NCATS NIH HHS
• KL2 TR003108 NCATS NIH HHS

Engineered T cell receptor T (TCR-T) cell therapy has facilitated the generation of increasingly reliable tumor antigen-specific adaptable cellular products for the treatment of human cancer. TCR-T cell therapies were initially focused on targeting shared tumor-associated peptide targets, including melanoma differentiation and cancer-testis antigens. With recent technological developments, it has become feasible to target neoantigens derived from tumor somatic mutations, which represents a highly personalized therapy, since most neoantigens are patient-specific and are rarely shared between patients. TCR-T therapies have been tested for clinical efficacy in treating solid tumors in many preclinical studies and clinical trials all over the world. However, the efficacy of TCR-T therapy for the treatment of solid tumors has been limited by a number of factors, including low TCR avidity, off-target toxicities, and target antigen loss leading to tumor escape. In this review, we discuss the process of deriving tumor antigen-specific TCRs, including the identification of appropriate tumor antigen targets, expansion of antigen-specific T cells, and TCR cloning and validation, including techniques and tools for TCR-T cell vector construction and expression. We highlight the achievements of recent clinical trials of engineered TCR-T cell therapies and discuss the current challenges and potential solutions for improving their safety and efficacy, insights that may help guide future TCR-T studies in cancer.

• T-cell receptor (TCR)
• cancer treatment
• clinical trials
• engineered TCR-T cell therapy
• tumor antigen

• Animals
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• CD8-Positive T-Lymphocytes/transplantation
• Humans
• Immunotherapy, Adoptive/adverse effects
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• Receptors, Chimeric Antigen/genetics
• Receptors, Chimeric Antigen/metabolism
• Treatment Outcome
• Tumor Microenvironment

Oral squamous cell carcinoma (OSCC) is a common tumor of the head and neck. Its treatment usually requires multiple modalities. Currently, there are no molecular biomarkers to guide these treatment strategies. Studies have shown that microfibril-associated protein 4 (MFAP4) is potentially useful for non-invasive assessment of various diseases; however, its biological function in tumors is still unknown. In this study, we propose that MFAP4 is a new prognostic target for OSCC.

First, we collected OSCC data (GSE25099 and GSE30784 datasets) from the Gene Expression Omnibus (GEO) database and compared the differential expression of MFAP4 gene between the patients (tumor) and normal (control) groups. The comparison was done with University of California Santa Cruz Xena (https://xenabrowser.net/Datapages/), and we calculated the difference in MFAP4 gene expression between normal and tumor tissues in a pan-cancer analysis. Then, we compared the 2 groups with high and low expression of MFAP4 gene in terms of tumor mutation burden (TMB), miRNA regulation, and immune cell infiltration.

We found that the expression of MFAP4 gene was significantly decreased in tumors. Our research also showed that high expression of MFAP4 was related to better prognosis of patients and may be related to tumor gene mutation, miRNA regulation, and infiltration of different immune cells.

Our work provides evidence that expression of MFAP4 can be used as a prognostic biomarker for risk stratification of OSCC patients and elaborates on its relation with the regulation of TMB, miRNAs, and immune cell infiltration.

Cancer immunotherapy is hampered by the immunosuppression maintained by regulatory T cells (Tregs) in tumor-bearing hosts. Stimulation of the Toll-like receptor 2 (TLR2) by Pam3Cys is known to affect Treg-mediated suppression. We found that Pam3Cys increases the proliferation of both CD4⁺ effector T cells (Teffs) and Tregs co-cultured in vitro, but did not induce the proliferation of Tregs alone upon CD3 and CD28 stimulation. In a mouse model of RMA-MUC1 tumors, Pam3Cys was administered either alone or in combination with a modified vaccinia ankara (MVA)-based mucin 1 (MUC1) therapeutic vaccine. The combination of Pam3Cys with MVA-MUC1 (1) diminished splenic Treg/CD4⁺ T-cell ratios to those found in tumor-free mice, (2) stimulated a specific anti-MUC1 interferon γ (IFNγ) response and (3) had a significant therapeutic effect on tumor growth and mouse survival. When CD4⁺ Teffs and Tregs were isolated from Pam3Cys-treated mice, Teffs had become resistant to Treg-mediated suppression while upregulating the expression of BclL-x_L. Tregs from Pam3Cys-treated mice were fully suppressive for Teffs from naïve mice. Bcl-x_L was induced by Pam3Cys with different kinetics in Tregs and Teffs. Teff from Pam3Cys-treated mice produced increased levels of Th1 and Th2-type cytokines and an interleukin (IL)-6-dependent secretion of IL-17 was observed in Teff:Treg co-cultures, suggesting that TLR2 stimulation had skewed the immune response toward a Th17 profile. Our results show for the first time that in a tumor-bearing host, TLR2 stimulation with Pam3Cys affects both Tregs and Teffs, protects Teff from Treg-mediated suppression and has strong therapeutic effects when combined with an MVA-based antitumor vaccine.

• TCR - T cell receptor
• adoptive T cell immunotherapy
• cancer immunoediting
• cancer immunotherapy
• genetic engineering

• Animals
• Gene Editing
• Gene Transfer Techniques
• Genetic Therapy/adverse effects
• Humans
• Immunotherapy, Adoptive/adverse effects
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• Receptors, Chimeric Antigen/genetics
• Receptors, Chimeric Antigen/immunology
• Receptors, Chimeric Antigen/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• T-Lymphocytes/transplantation
• Treatment Outcome

Considering the limited progress of chemotherapy and targeted therapy in improving the generally disappointing outcomes of advanced gastric or gastroesophageal junction cancer (GC/GEJC), immunotherapies have been gradually developed and advanced into novel frontiers of treatment for advanced GC/GEJC. Nevertheless, the response to immunotherapy was not always satisfactory, and the emergence of resistance was unavoidable. These factors prompt the development of different combination therapies and predictive and prognostic biomarkers of efficacy to improve the outcomes of patients with advanced GC/GEJC and to overcome drug resistance. This article discusses the advances of immune monotherapy, multiple current and ongoing clinical trials of immune combination therapy, immune-related adverse events, and various biomarkers in GC/GEJC.

• biomarkers
• combination therapy
• gastric or gastroesophageal junction cancer
• immune related adverse events
• immunotherapy

• T cell receptor
• adoptive T cell therapy
• intracellular targets
• pHLA complex

• Cancer immunotherapy
• Chimeric antigen receptor
• Gene therapy
• Osteosarcoma
• Pediatric cancer
• T-cell therapy
• Tumor antigens

• <italic>MAGEA3</italic>
• <italic>MAGEA6</italic>
• Bidirectional promoter
• Cancer-germline genes
• Genome misassembly
• Segmental duplication

• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/metabolism
• Chromosomes, Human, X/genetics
• Epigenesis, Genetic/genetics
• Gene Duplication/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Genome, Human/genetics
• Humans
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/pathology
• Promoter Regions, Genetic/genetics
• Receptors, GABA-A/genetics
• Segmental Duplications, Genomic/genetics
• Tumor Cells, Cultured

• STING agonists
• cancer immunotherapy
• co-delivery
• mRNA vaccines
• nanocarriers
• nanovaccine
• neoantigen vaccines

• Cancer Vaccines/immunology
• Drug Carriers/chemistry
• Drug Delivery Systems
• Humans
• Immunotherapy
• Nanomedicine
• Neoplasms/immunology
• Neoplasms/therapy

• R01 CA229812 NCI NIH HHS
• UL1 TR002649 NCATS NIH HHS
• R01 CA099326 NCI NIH HHS
• R01 CA175033 NCI NIH HHS
• UL1TR002649 NCATS NIH HHS
• P30 CA106059 NIH HHS
• R43 CA106059 NCI NIH HHS
• KL2 TR002648 NCATS NIH HHS

• Heat shock proteins
• anticancer vaccine
• chaperones
• immune response
• tumor- specific antigens
• tumor-associated antigens.

• dendritic cells
• immunoediting
• immunogenic tumor
• melanoma

• dendritic cells
• immunoediting
• immunogenic tumor
• melanoma

Gastric cancer is the second most common cause of cancer-related mortality; thus, the mechanisms underlying tumor metastasis and growth in gastric cancer need to be extensively explored.

Differentially expressed genes were examined in gastric cancer samples with lymph node metastasis (LNM) and without LNM using mRNA microarray and RT-qPCR. The effects of G antigen 7B (GAGE7B) on the metastasis, growth, and angiogenesis of gastric cancer were investigated in vitro and in vivo. GAGE7B protein expression was detected by immunohistochemical (IHC) analysis. Microarray, RT-qPCR, and western blot assays were performed to detect downstream target genes of GAGE7B. Dual-luciferase reporter and western blot assays were used to identify miRNAs that could negatively regulate GAGE7B.

GAGE7B was significantly overexpressed in samples with LNM. High expression levels of GAGE7B were associated with advanced clinical stage and poor patient survival. GAGE7B dramatically enhanced the metastasis, growth, and angiogenesis ability of gastric cancer. GAGE7B was further demonstrated to promote the progression of gastric cancer by activating the p38δ/pMAPKAPK2/pHSP27 pathway. However, the GAGE7B-induced p38δ/pMAPKAPK2/pHSP27 pathway was inactivated by miR-30c, as the expression levels of both GAGE7B and p38δ were found to be directly suppressed by miR-30c. Intriguingly, GAGE7B was found to be a ceRNA for p38δ, as it activated the p38δ/pMAPKAPK2/pHSP27 pathway by competitively binding miR-30c.

GAGE7B may serve as a prognostic indicator in gastric cancer. GAGE7B significantly promotes gastric cancer progression by upregulating the p38δ/pMAPKAPK2/pHSP27 pathway, but it is negatively regulated by miR-30c. GAGE7B and miR-30c may be potential therapeutic targets in gastric cancer.

The online version of this article (10.1186/s13046-019-1125-z) contains supplementary material, which is available to authorized users.

• GAGE7B
• Gastric cancer
• Growth
• Metastasis

• Immunogenic cell death (ICD)
• Immunotherapy
• Microsatellite instability
• PD-1
• Tumor microenvironment

• Antineoplastic Agents, Immunological/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• DNA Mismatch Repair
• Humans
• Immunotherapy
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/immunology
• Liver Neoplasms/secondary
• Microsatellite Instability

• P30 CA047904 NCI NIH HHS
• U01 CA099168 NCI NIH HHS

• CTLA-4
• MAGE-A
• PD-1
• autophagy
• cancer-germline antigen
• checkpoint blockade
• immunogenomics
• immunotherapy
• ipilimumab
• melanoma

• T-cell receptor
• TCR-engineered T cells
• neoantigen
• tumor antigen
• tumor microenvironment

• Animals
• Antigens, Neoplasm/immunology
• Antigens, Neoplasm/metabolism
• Humans
• Neoplasms/immunology
• Neoplasms/metabolism
• Receptors, Antigen, T-Cell/genetics
• Receptors, Antigen, T-Cell/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism

• Bone Marrow
• Distant Metastasis.
• Lung Cancer
• MAGE A1-6
• Recurrence
• Survival Rate

In a previously reported study, patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab (ipi) (Tarhini in PLoS ONE 9(2): e87705, 3). Significant changes in circulating myeloid derived suppressor cells (MDSC), regulatory T cells (Treg) and peptide specific type I CD4⁺ and CD8⁺ T cells were noted at week 6 that correlated with clinical outcome. Characterization of antigen-specific effector T cell secreted cytokines may shed insights into ipi associated T cell activation and function.

Patients were treated with neoadjuvant ipi (10 mg/kg every 3 weeks ×2) administered intravenously before and after surgery. Peripheral blood mononuclear cells (PBMC) that were collected at baseline and week 6 (after ipi) were tested here. Each sample was divided into 5 groups and stimulated with controls or shared melanoma antigen overlapping peptide pools (NY-ESO 1, gp-100, MART-1). Secreted cytokines, chemokines and growth factors were assessed using Luminex. Cytokine expression levels between the 3 antigen groups were compared using the Wilcox rank-sum test.

Seventeen cytokines were differentially expressed with stimulation by each antigen at baseline (p value <0.05): IL1β, MIP1β, IL1RA, VEGF, IL13, IL17, MIP1α, GM-CSF, MCP1, IL5, IL2R, IL4, IL10, IFNγ, TNFα, IL8 and IL2. At week 6, 15 cytokines were differentially expressed (p < 0.05): IL1β, VEGF, G-CSF, HGF, IL13, IL17, GM-CSF, MCP1, IL5, IL7, IL4, IL10, IFNγ, IL8 and IL2. Patients were later clustered based on cytokine expression levels at baseline and at week 6, and recurrence free survival (RFS) was compared. Clear differences in RFS were noted based on cytokine level clustering both at baseline and at week 6: Patients whose PBMCs secreted more cytokines in response to NY-ESO-1 showed a trend towards better RFS.

PBMCs of patients treated with ipi secreted significantly more cytokines, chemokines and growth factors in response to NY-ESO-1 than to gp-100 or MART-1. These cytokines belonged to different functional groups, including inflammatory, type 1, type 2 and regulatory, that warrant further study. Patients whose PBMCs secreted more cytokines (particularly in response to NY-ESO-1) tended to have better RFS, supporting further exploration in terms of therapeutic predictive value.

The online version of this article (doi:10.1186/s12967-017-1140-9) contains supplementary material, which is available to authorized users.

• Cytokines
• Ipilimumab
• Melanoma
• Neoadjuvant

• Autoreactive T cells
• CD1
• CpG
• self-lipids
• tumor immunity

• Anti-tumor effects
• Antigen specific-CD8 T-cells
• Peptide/poly-IC vaccine
• Zoledronic acid (ZA)

Peptide-based vaccines are attractive approaches for cancer immunotherapy; but the success of these vaccines in clinical trials have been limited. Our goal is to improve immune responses and anti-tumor effects against a synthetic, multi-epitope, long peptide from rat Her2/neu (rHer2/neu) using the help of CD4+ T cells and appropriate adjuvant in a mouse tumor model. Female BALB/c mice were vaccinated with P₅₊₄₃₅ multi-epitope long peptide that presents epitopes for cytotoxic T lymphocytes (CTL) in combination with a universal Pan DR epitope (PADRE) or CpG-oligodeoxynucleotides (CpG-ODNs) as a Toll-like receptor agonist adjuvant. The results show that vaccination with the multi-epitope long peptide in combination with the PADRE peptide and CpG-ODN induced expansion of subpopulations of CD4+ and CD8+ cells producing IFN-γ, the average tumor size in the vaccinated mice was less than that of the other groups, and tumor growth was inhibited in 40% of the mice in the vaccinated group. The mean survival time was 82.6 ± 1.25 days in mice vaccinated with P₅₊₄₃₅ + CpG+ PADRE. Our results demonstrate that inclusion of PADRE and CpG with the peptide vaccine enhanced significant tumor specific-immune responses in vaccinated mice.

Many human tumors show aberrant activation of a group of germline-specific genes, termed cancer-germline (CG) genes, several of which appear to exert oncogenic functions. Although activation of CG genes in tumors has been linked to promoter DNA demethylation, the mechanisms underlying this epigenetic alteration remain unclear. Two main processes have been proposed: awaking of a gametogenic program directing demethylation of target DNA sequences via specific regulators, or general deficiency of DNA methylation activities resulting from mis-targeting or down-regulation of the DNMT1 methyltransferase.

By the analysis of transcriptomic data, we searched to identify gene expression changes associated with CG gene activation in melanoma cells. We found no evidence linking CG gene activation with differential expression of gametogenic regulators. Instead, CG gene activation correlated with decreased expression of a set of mitosis/division-related genes (ICCG genes). Interestingly, a similar gene expression signature was previously associated with depletion of DNMT1. Consistently, analysis of a large set of melanoma tissues revealed that DNMT1 expression levels were often lower in samples showing activation of multiple CG genes. Moreover, by using immortalized melanocytes and fibroblasts carrying an inducible anti-DNMT1 small hairpin RNA (shRNA), we demonstrate that transient depletion of DNMT1 can lead to long-term activation of CG genes and repression of ICCG genes at the same time. For one of the ICCG genes (CDCA7L), we found that its down-regulation in melanoma cells was associated with deposition of repressive chromatin marks, including H3K27me3.

Together, our observations point towards transient DNMT1 depletion as a causal factor of CG gene activation in vivo in melanoma.

The online version of this article (doi:10.1186/s13148-015-0147-4) contains supplementary material, which is available to authorized users.

DNA vaccination has emerged as an attractive immunotherapeutic approach against cancer due to its simplicity, stability, and safety. Results from numerous clinical trials have demonstrated that DNA vaccines are well tolerated by patients and do not trigger major adverse effects. DNA vaccines are also very cost effective and can be administered repeatedly for long-term protection. Despite all the practical advantages, DNA vaccines face challenges in inducing potent antigen specific cellular immune responses as a result of immune tolerance against endogenous self-antigens in tumors. Strategies to enhance immunogenicity of DNA vaccines against self-antigens have been investigated including encoding of xenogeneic versions of antigens, fusion of antigens to molecules that activate T cells or trigger associative recognition, priming with DNA vectors followed by boosting with viral vector, and utilization of immunomodulatory molecules. This review will focus on discussing strategies that circumvent immune tolerance and provide updates on findings from recent clinical trials.

• APCs, antigen presenting cells
• CEA, carcinoembryonic antigen
• CIN, cervical intraepithelial neoplasia
• CT antigens, cancer-testis antigens
• CTLs, cytotoxic lymphocytes
• DNA vaccines
• DOM, fragment c domain
• EP, electroporation
• GITR, glucocorticoid-induced tumor necrosis factor receptor family-related genes
• HER2, Her2/neu
• HSP70, heat shock protein 70
• IFNs, interferons
• IRF, interferon regulatory factor
• Id, idiotype
• MHC, major histocompatibility complex
• Mam-A, Mammaglobin-A
• NHP, non-human primate
• PAP, Prostatic acid phosphatase
• PMED, particle mediated epidermal delivery
• PSMA, prostate-specific membrane antigen
• SCT, single-chain trimer
• STING, stimulator of interferon genes
• TAAs, tumor-associated antigens
• TBK1, Tank-binding kinase 1
• TLRs, Toll-like receptors
• TT, tetanus toxin
• Trp2, tyrosinase related protein 2
• cellular immune response
• hTERT, human telomerase reverse transcriptase
• humoral immune response
• immune tolerance
• phTERT, optimized full-length hTERT
• tumor antigens
• vaccine delivery

• SELEX
• aptamer
• shared tumor-specific antigen

• Check-points immunitaires
• Immune check-points
• Immunomodulation
• Radiosensiblisation
• Radiosenzitisation
• Radiotherapy
• Radiothérapie

• Adult
• Aged
• Aged, 80 and over
• Cohort Studies
• Female
• Humans
• Lymph Nodes/immunology
• Lymph Nodes/pathology
• Lymphatic Metastasis
• Lymphocytes, Tumor-Infiltrating/immunology
• Male
• Melanoma/immunology
• Melanoma/mortality
• Melanoma/pathology
• Middle Aged
• Multivariate Analysis
• Prognosis
• Proportional Hazards Models
• Sentinel Lymph Node Biopsy
• Skin Neoplasms/immunology
• Skin Neoplasms/mortality
• Skin Neoplasms/pathology
• Survival Rate
• Young Adult
• Melanoma, Cutaneous Malignant

• Cancer immunotherapy
• Checkpoint inhibition
• Immune activation
• Immunoediting
• Immunosuppression
• T lymphocyte
• Tumour escape

• Animals
• Antigens, Neoplasm/immunology
• Bystander Effect/immunology
• Cell Communication/immunology
• Cell Transformation, Neoplastic/immunology
• Cell Transformation, Neoplastic/metabolism
• Cell- and Tissue-Based Therapy
• Genetic Engineering
• Genetic Therapy
• Humans
• Immunologic Factors/pharmacology
• Immunologic Factors/therapeutic use
• Immunomodulation
• Immunotherapy/methods
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• Signal Transduction
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/metabolism
• T-Lymphocytes, Regulatory/immunology
• Tumor Escape/immunology
• Tumor Microenvironment/immunology

• P50 CA 090949 NCI NIH HHS
• U54 CA163069 NCI NIH HHS
• G12 MD007586 NIMHD NIH HHS
• SC1 CA182843 NCI NIH HHS
• R01 CA175370 NCI NIH HHS
• P50 CA090949 NCI NIH HHS
• R01 CA175370. NCI NIH HHS
• P20 CA192976 NCI NIH HHS
• P20CA192976 NCI NIH HHS
• U54 MD007593 NIMHD NIH HHS

The proteasome is responsible for the breakdown of cellular proteins. Proteins targeted for degradation are allowed inside the proteasome particle, where they are cleaved into small peptides and released in the cytosol to be degraded into amino acids. In vertebrates, some of these peptides escape degradation in the cytosol, are loaded onto class I molecules of the major histocompatibility complex (MHC) and displayed at the cell surface for scrutiny by the immune system. The proteasome therefore plays a key role for the immune system: it provides a continued sampling of intracellular proteins, so that CD8-positive T-lymphocytes can kill cells expressing viral or tumoral proteins. Consequently, the repertoire of peptides displayed by MHC class I molecules at the cell surface depends on proteasome activity, which may vary according to the presence of proteasome subtypes and regulators. Besides standard proteasomes, cells may contain immunoproteasomes, intermediate proteasomes and thymoproteasomes. Cells may also contain regulators of proteasome activity, such as the 19S, PA28 and PA200 regulators. Here, we review the effects of these proteasome subtypes and regulators on the production of antigenic peptides. We also discuss an unexpected function of the proteasome discovered through the study of antigenic peptides: its ability to splice peptides.

• cancer
• cytotoxic T cell
• dendritic cell
• mRNA
• tumor antigen