• case report
• gastric cancer
• immunotherapy
• microsatellite instability high
• mismatch repair-deficient

• Borrmann type
• Gastric cancer
• Immunotherapy
• Neoadjuvant therapy
• Tumor regression grade

• gastric cancer
• immunotherapy
• targeted therapy

• autophagy
• gastric cancer
• molecular features
• oxidative stress
• tumor microenvironment

• Humans
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Tumor Microenvironment/genetics
• Autophagy/genetics
• Fluorouracil
• Afatinib
• Prognosis

Gastric cancer is one of the most common malignant tumours worldwide, with the fifth and third highest morbidity and mortality, respectively, of all cancers. Survival is limited, as most of the patients are diagnosed at an advanced stage, and are not suitable for surgery with a curative intent. Chemotherapy has only modestly improved patients’ outcomes and is mainly given with a palliative intent. Immunotherapy has improved overall survival of patients with gastric cancer, and has thus become a new standard of care in clinic. In this review we discuss the strong molecular rationale for the administration of immunotherapy in this disease and analyse the clinical data supporting its use.

Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer.

• epithelial-mesenchymal transition
• gastric cancer
• microsatellite instability-high
• prognosis
• tumor microenvironment

Antibodies against programmed death 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1) have recently shown promising results in gastric cancer (GC). However, clinicians still lack predictive biomarkers for the efficacy of anti-PD-1 therapy; thus, we investigated the expression of PD-L1 in GC and further assessed its clinical relevance with other clinicopathological features.

We retrospectively collected clinical data on 968 consecutive GC cases from Nanfang Hospital between November 2018 and August 2021. Discrepancy in the combined positive score (CPS) of PD-L1 protein expression between gastric mucosa biopsy and postoperative pathology were investigated. Correlations between CPS and clinicopathological parameters were determined using chi-squared test, multiple logistic aggression analysis, and linear regression analysis.

Among the 968 consecutive GC patients, 199 who did not receive preoperative chemotherapy or immunotherapy were tested for CPS both in gastric mucosa biopsy and postoperative pathology, and the results showed that the CPS of gastric mucosa biopsy was significantly lower than that of postoperative pathology [mean ± SD: 5.5 ± 9.4 vs. 13.3 ± 17.4; M(IQR): 2(5) vs. 5(12), p<0.001)]. 62.3% of patients (579/930) had CPS≥ 1, 49.2% of patients (458/930) had CPS≥5, and 33.3% of patients (310/930) had CPS≥10. Mismatch repair deficiency (dMMR) status was seen in 6.1% of patients (56 of 919). Positive Epstein–Barr virus (EBV) status was detected in 4.4% of patients (38 of 854). The patients with CPS≥1/CPS≥5/CPS≥10 were significantly independently correlated with age, Lauren classification, Ki-67 index, and EBV status. According to linear regression analysis, PD-L1 expression was correlated with age (p<0.001), Ki-67 index (p<0.001), EBV (p<0.001), and Lauren classification (p=0.002).

Our results confirmed that PD-L1 expression has Intratumoral heterogeneity in GC. Furthermore, the variables of age, Ki-67 index, and Lauren classification, which are common and accessible in most hospitals, are worth exploring as potential biomarkers for anti-PD-1 therapy in GC.

• CPS
• Ki-67
• PD-L1
• biopsy
• gastric cancer
• pathology

• B7-H1 Antigen/genetics
• B7-H1 Antigen/metabolism
• Humans
• Immunotherapy/methods
• Ligands
• Neoplasms/genetics
• Neoplasms/therapy
• Prognosis

• Gastric adenocarcinoma
• Molecular classification
• PDL1

• Research Dean of Shiraz University of Medical Sciences
• 0

• 5-fluorouracil
• colorectal adenocarcinoma
• inflammation
• metastasis
• zotarolimus

• Animals
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis
• Cell Proliferation
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Fluorouracil/administration & dosage
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Sirolimus/administration & dosage
• Sirolimus/analogs & derivatives
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• carcinogenesis
• early gastric cancer
• gastric dysplasia

• Aged
• Aged, 80 and over
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor/analysis
• Carcinogenesis/genetics
• Epstein-Barr Virus Infections/complications
• Epstein-Barr Virus Infections/pathology
• Female
• Humans
• Immunohistochemistry
• In Situ Hybridization
• Male
• Microsatellite Instability
• Middle Aged
• Neoplasm Grading
• Stomach Neoplasms/classification
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• World Health Organization

We sought to determine if Stephen Paget’s “seed and soil” hypothesis of organ-preference patterns of cancer metastasis can explain the development of heterogeneity in a tumor microenvironment (TME) as well as immunotherapeutic delivery and efficacy. We established single-cell-derived clones (clones 1 and 16) from parental 4T1 murine breast cancer cells to create orthotopic primary and liver metastasis models to deconvolute polyclonal complexity cancer cells and the difference in TME-derived heterogeneities. Tumor-bearing mice were treated with anti-PD-L1 IgG or a control antibody, and immunofluorescent imaging and quantification were then performed to evaluate the therapeutic efficacy on tumor growth, the delivery of therapy to tumors, the development of blood vessels, the expression of PD-L1, the accumulation of immune cells, and the amount of coagulation inside tumors. The quantification showed an inverse correlation between the amount of delivered therapy and therapeutic efficacy in parental-cell-derived tumors. In contrast, tumors originating from clone 16 cells accumulated a significantly greater amount of therapy and responded better than clone-1-derived tumors. This difference was greater when tumors grew in the liver than the primary site. A similar trend was found in PD-L1 expression and immune cell accumulation. However, the change in the number of blood vessels was not significant. In addition, the amount of coagulation was more abundant in clone-1-derived tumors when compared to others. Thus, our findings reconfirmed the seed- and soil-dependent differences in PD-L1 expression, therapeutic delivery, immune cell accumulation, and tumor coagulation, which can constitute a heterogeneous delivery and response of immunotherapy in polyclonal tumors growing in different organs.

• drug delivery
• heterogeneity
• immunotherapy
• tumor microenvironment

• UO1 CA244107 NCI NIH HHS
• U54 CA210181 NCI NIH HHS

• Cancer immunotherapy
• Combination therapy
• Small molecule inhibitors
• Tumor microenvironment

• Microsatellite instability
• chemotherapy
• gastric cancer
• immunotherapy
• mismatch repair

• CPS
• Esophageal tumor
• Gastric tumor
• Gastroesophageal junction tumor
• Gastroesophageal tumor
• HER2
• Immunotherapy
• PD-L1
• TPS

• Adult
• Aged
• Aged, 80 and over
• B7-H1 Antigen/genetics
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Case-Control Studies
• Combined Modality Therapy
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/therapy
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• Prognosis
• Receptor, ErbB-2/genetics
• Receptor, ErbB-2/metabolism
• Retrospective Studies
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy
• Survival Rate

• n.a. Medizinische Universität Wien

The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials.

We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines.

PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. “Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8^+/low tumor-infiltrating lymphocytes (TILs),” and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3^+/low TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3^+/high TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(−) cell lines.

The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of “tumoral PD-L1/immune cell PD-L1/CD8⁺ TILs” may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(−)/CD8^+/low TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.

• Epstein-Barr virus
• Microsatellite instability
• PD-L1
• Prognosis
• Stomach cancer
• Tumor-infiltrating lymphocytes

• Biomarker
• Microsatellite instability
• Prognosis
• Recurrence
• Stomach neoplasms

Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

• Cancer immunotherapy
• Immune cells
• Immune checkpoint blockade
• PD-1/PD-L1
• Precision medicine

• chemotherapy
• gastric cancer
• gastroesophageal cancer
• immunotherapy
• targeted therapy

We aimed to evaluate the clinical characteristics of microsatellite instability in early gastric cancer.

The microsatellite instability status of resected early gastric tumors was evaluated using two mononucleotide repeat markers (BAT25 and BAT26) and three dinucleotide repeat markers (D5S346, D2S123, and D17S250). Tumors with instability in two or more markers were defined as microsatellite instability-high (MSI-H) and others were classified as microsatellite stable (MSS).

Overall, 1,156 tumors were included in the analysis, with 85 (7.4%) classified as MSI-H compared with MSS tumors. For MSI-H tumors, there was a significant correlation with the female sex, older age, tumor location in the lower gastric body, intestinal histology, lymphovascular invasion (LVI), and submucosal invasion (P<0.05). There was also a trend toward an association with lymph node (LN) metastasis (P=0.056). In mucosal gastric cancer, there was no significant difference in MSI status in tumors with LN metastasis or tumors with LVI. In submucosal gastric cancer, LVI was more frequently observed in MSI-H than in MSS tumors (38.9% vs. 25.0%, P=0.027), but there was no difference in the presence of LN metastases. The prognosis of MSI-H tumors was similar to that of MSS tumors (log-rank test, P=0.797, the hazard ratio for MSI-H was adjusted by age, sex, pT stage, and the number of metastatic LNs, 0.932; 95% confidence interval, 0.423–2.054; P=0.861).

MSI status was not useful in predicting prognosis in early gastric cancer. However, the frequent presence of LVI in early MSI-H gastric cancer may help guide the appropriate treatment for patients, such as endoscopic treatment or limited LN surgical dissection.

• Gastric cancer
• Lymph nodes
• Microsatellite instability
• Prognosis

Gastric cancer (GC) is one of the most important malignancies worldwide because of its high incidence and mortality. The very low survival rates are mainly related to late diagnosis and limited treatment options. GC is the final clinical outcome of a stepwise process that starts with a chronic and sustained inflammatory reaction mounted in response to Helicobacter pylori infection. The bacterium modulates innate and adaptive immunity presumably as part of the strategies to survive, which favors the creation of an immunosuppressive microenvironment that ultimately facilitates GC progression. T-cell exhaustion, which is characterized by elevated expression of immune checkpoint (IC) proteins, is one of the most salient manifestations of immunosuppressive microenvironments. It has been consistently demonstrated that the tumor-immune microenvironment(TIME)‐exhausted phenotype can be reverted by blocking ICs with monoclonal antibodies. Although these therapies are associated with long-lasting response rates, only a subset of patients derive clinical benefit, which varies according to tumor site. The search for biomarkers to predict the response to IC inhibition is a matter of intense investigation as this may contribute to maximize disease control, reduce side effects, and minimize cost. The approval of pembrolizumab for its use in GC has rocketed immuno-oncology research in this cancer type. In this review, we summarize the current knowledge centered around the immune contexture and recent findings in connection with IC inhibition in GC.

• anti-PD-L1 antibody
• colorectal cancer
• doxorubicin
• gold nanoparticles

• ARID1A
• PD-L1
• gastric cancer
• immunotherapy
• microsatellite instability

• Case report
• Gastric cancer
• Liver metastases
• Long-term survival
• Treatment

Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.

• checkpoint inhibitors
• esophageal cancer
• gastric cancer
• immunotherapy
• microsatellite instability

• Gastric carcinoma
• MET
• Microsatellite instability-high
• Programmed death-ligand 1

• Epstein–Barr virus-associated gastric cancer
• Immune genes
• PD-L1

• Gastric cancer
• HLA-G
• Immunoescape
• MHC

• Adenocarcinoma/immunology
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Adenocarcinoma/therapy
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/analysis
• Female
• HLA-G Antigens/analysis
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Proportional Hazards Models
• Risk Factors
• Stomach Neoplasms/immunology
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy
• Time Factors
• Treatment Outcome
• Tumor Escape

The use of four groups of tumor immune microenvironments (TME) based on PD-L1 and tumor-infiltrating T lymphocytes (TIL) is a reliable biomarker for anti-PD-1/PD-L1 inhibitor therapy. We classified the TME in 241 gastric cancers which were subdivided according to 40 EBV+, 76 microsatellite instability-high (MSI-H), and 125 EBV-/microsatellite-stable (MSS) subtypes by quantitative image analysis (QIA) and correlated the results with mRNA expression levels. The mean PD-L1 ratio and CD8 ratio in EBV+, MSI-H, and EBV−/MSS GCs were significantly different (P < 0.006). The PD-L1 ratio and CD8 ratio obtained by QIA correlated well with the RNA levels of PD-L1 (r = 0.63) and CD8 (r = 0.67), respectively. The TME were type I (PD-L1^H/CD8^H) in 45, type II (PD-L1^L/CD8^L) in 106, type III (PD-L1^H/CD8^L) in 8, and type IV (PD-L1^L/CD8^H) in 82 cases. The type I TME was significantly associated with high TIL (P = 3.0E-11) and EBV+ status (P = 8.55E-08). In conclusion, QIA results correlated well with the mRNA expression levels and classified TME of gastric cancers.

• PD-L1
• Tregs
• immunity
• tristetraprolin
• tumor progression

• Apoptosis
• B7-H1 Antigen/genetics
• B7-H1 Antigen/metabolism
• CD8-Positive T-Lymphocytes/immunology
• Cell Line, Tumor
• Cell Survival
• Disease Progression
• Female
• Forkhead Transcription Factors/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Immunity
• Leukocytes, Mononuclear/metabolism
• Male
• Middle Aged
• Multivariate Analysis
• RNA Stability
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Stomach Neoplasms/genetics
• Stomach Neoplasms/immunology
• Stomach Neoplasms/pathology
• Survival Analysis
• T-Lymphocytes, Regulatory/immunology
• Tristetraprolin/genetics
• Tristetraprolin/metabolism

• Immunohistochemistry
• Malignant pleural mesothelioma
• Microsatellite instability
• Mismatch repair protein
• PD-L1

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

• PD-1
• PD-L1
• colorectal cancer
• prognosis
• programmed cell death receptor
• sidedness
• tumour location

Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2.

Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov. Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers.

Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy.

Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.

• Cancer treatment
• Chemotherapy
• Colorectal cancer
• Immunotherapy
• Lynch syndrome
• Microsatellite instability
• Mismatch repair

• Clinical trials
• Gastric cancer
• Immunotherapy
• Molecular classification
• Targeted therapy

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/analysis
• Drug Resistance, Neoplasm/genetics
• Gastrectomy
• Genomics
• Humans
• Molecular Targeted Therapy/methods
• Neoplasm Recurrence, Local/genetics
• Neoplasm Recurrence, Local/mortality
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/therapy
• Patient Selection
• Precision Medicine/methods
• Quality of Life
• Stomach/pathology
• Stomach/surgery
• Stomach Neoplasms/genetics
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy

• Immunotherapy
• Intratumoral heterogeneity
• Thymic carcinoma
• Thymoma

• Adult
• Aged
• B7-H1 Antigen/biosynthesis
• B7-H1 Antigen/immunology
• Female
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Neoplasms, Glandular and Epithelial/immunology
• Neoplasms, Glandular and Epithelial/metabolism
• Neoplasms, Glandular and Epithelial/pathology
• Prognosis
• Programmed Cell Death 1 Receptor/biosynthesis
• Programmed Cell Death 1 Receptor/immunology
• Retrospective Studies
• Thymoma/immunology
• Thymoma/metabolism
• Thymoma/pathology
• Thymus Neoplasms/immunology
• Thymus Neoplasms/metabolism
• Thymus Neoplasms/pathology

• P30 CA016058 NCI NIH HHS

• mismatch repair genes
• molecular
• stomach cancer
• surgery

• Aged
• Aged, 80 and over
• DNA Mismatch Repair/genetics
• Female
• Humans
• Male
• Microsatellite Instability
• Middle Aged
• Retrospective Studies
• Stomach Neoplasms/genetics
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery

• Disease Progression
• Humans
• Immunity/immunology
• Lymphatic Metastasis/immunology
• Prognosis
• Stomach Neoplasms/immunology
• Stomach Neoplasms/pathology
• T-Lymphocytes/immunology

During their development and progression tumors acquire numerous mutations that, when translated into proteins give rise to neoantigens that can be recognized by T cells. Initially, neoantigens were not recognized as preferred targets for cancer immunotherapy due to their enormous diversity and the therefore limited options to develop “one fits all” pharmacologic solutions. In recent years, the experience obtained in clinical trials demonstrating a predictive role of neoantigens in checkpoint inhibition has changed our view on the clinical potential of neoantigens in cancer immunotherapy. Technological advances such as sequencing of whole cancer genomes, the development of reliable algorithms for epitope prediction, and an increasing number of immunotherapeutic options now facilitate the development of personalized tumor therapies directly targeting a patient’s neoantigenic burden. Preclinical studies in mice that support the excellent therapeutic potential of neoantigen-directed immunotherapies have provided blueprints on how this methodology can be translated into clinical applications in humans. Consistently, very recent clinical studies on personalized vaccinations targeting in silico predicted neoepitopes shed a first light on the therapeutic potential of personalized, neoantigen-directed immunotherapies. In our review, we discuss the various subtypes of tumor antigens with a focus on neoantigens and their potential in cancer immunotherapy. We will describe the current methods and techniques of detection as well as the structural requirements for neoantigens that are needed for their recognition by T cells and for tumor destruction. To assess the clinical potential of neoantigens, we will discuss their occurrence and functional relevance in spontaneous and hereditary cancers and their prognostic and predictive value. We will present in detail the existing immunotherapeutic options that exploit the neoantigen burden of tumors encompassing both preclinical efforts that provided convincing technological proof-of-concept and the current clinical studies confirming the potential of neoantigen-directed immunotherapies.

• adoptive transfer
• mutations
• neoantigens
• personalized cancer immunotherapy
• vaccination