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Gastric cancer ranks fifth in both world prevalence and lethality, with a 5-year survival of less than 30%. HLA-G, a non-classical class I HLA gene, has emerged as a potential marker for cancer susceptibility and prognosis due to its immunomodulatory properties. Its level of expression is regulated by polymorphisms in the 3' untranslated region (3'UTR) polymorphisms, which form various combined haplotypes (UTR-1 to -9). In this study, we examined HLA-G 3'UTR polymorphisms in paired tissue samples from 111 patients with gastric adenocarcinoma and 119 healthy controls. Polymorphism analysis was performed using PCR and Sanger sequencing, followed by statistical analysis using SNPStats software. Survival analysis was conducted using Kaplan-Meier curves and multivariate Cox regression models. High-expressor HLA-G 3'UTR haplotypes (UTR-1 and UTR-6) were significantly associated with gastric cancer susceptibility, indicating a potential role in tumor immune evasion. Additionally, the 14 base pair insertion/deletion polymorphism (14 bp I/D) emerged as a prognostic marker, with D/D genotype carriers showing lower survival rates compared to I/D and I/I genotype carriers. Our study highlights the clinical relevance of HLA-G polymorphisms in gastric cancer, suggesting their potential as prognostic markers and therapeutic targets. Further elucidation of HLA-G-related pathways could lead to personalized treatment strategies and improved patient outcomes in gastric cancer., Competing Interests: Declarations Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Human and animal rights The studies involving human participants were reviewed and approved by Comité ético de investigación clínica, Hospital Clínico San Carlos, Madrid, Spain. The patients/participants provided their written informed consent to participate in this study. Informed consent The study was performed in accordance with the ethical standards as laid down in the Declarations of Helsinki and approved by the local ethics committee. Written informed consent was obtained from all subjects., (© 2024. The Author(s).)

Background: Loss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy. However, there is no data on perioperative chemoimmunotherapy (ChIO) efficacy or response mechanisms in the context of HLA class I defects., Methods: Baseline HLA class I tumor status (HLA-deficient (HLA-DEF) or HLA-proficient (HLA-PRO)) was determined by DNA LOH combined with immunohistochemistry for protein levels in tissue of 24 patients with NSCLC treated with perioperative nivolumab plus chemotherapy from NADIM trial (NCT03081689). We integrated HLA tumor status with molecular data (programmed death-ligand 1 (PD-L1), TMB, TCR repertoire, TILs populations, bulk RNA-seq, and spatial transcriptomics (ST)) and clinical outcomes (pathological response and survival data) to study the activity of perioperative ChIO considering HLA class I defects., Results: HLA-DEF tumors comprised 41.7% of analyzed tumors and showed a desert-like microenvironment at baseline, with lower PD-L1 levels and reduced immune infiltrate. However, perioperative ChIO induced similar complete pathological response (CPR) rates in both HLA-DEF and PRO tumors (50% and 60% respectively, p=0.670), as well as 3-year survival rates: Progression-free survival (PFS) and overall survival (OS) of 70% (95% CI 32.9% to 89.2%) for HLA-DEF, and PFS 71.4% (95% CI 40.6% to 88.2%) and OS 92.9% (95% CI 59.1% to 99.0%) for HLA-PRO (log-rank PFS p=0.909, OS p=0.137). Proof-of-concept ST analysis of a CPR HLA-DEF tumor after ChIO showed a strong immune response with tertiary lymphoid structures (TLS), CD4+T cells with HLA class II colocalization, and activated CD8+T cells., Conclusions: Our findings highlight the activity of perioperative ChIO, and the potential role of TLS and T-cell immune response, in NSCLC HLA-DEF tumors., Competing Interests: Competing interests: VC reports consulting fees from Roche, AstraZeneca, MSD, BMS, Takeda, Sanofi, Agmen; payment or honoraria from Roche, AstraZeneca, MSD, BMS, Takeda, Sanofi, Agmen, Janssen, Regeneron and Pfizer; and support for attending meetings and/or travel from Roche, AstraZeneca, MSD, and Takeda outside the submitted work. EN reports grants from Roche, BMS, Pfizer, and Merck Serono; consulting fees and payment or honoraria form Roche, BMS, MSD, Merck Serono, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi Sankyo, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre, Qiagen; payment or honoraria from Bayer; and advisory board from MSD, Roche, Apollomics, Daiichi and Transgene outside the submitted work. AM-M reports consulting fees, payment or honoraria and support for attending meetings and/or travel from AstraZeneca/MedImmune, BMS, F Hoffmann-La Roche AG, MSD, MSD Oncology, Pfizer; Steering Committee Member of AstraZeneca/MedImmune; support for attending meetings and/or travel from Lilly; and advisory board from AstraZeneca/MedImmune, MSD, BMS, and F Hoffmann-La Roche AG outside the submitted work. AI reports consulting fees from Pfizer, Amgen, AstraZeneca, and Roche; payment form expert testimony form BMS, Roche, Pfizer, AstraZeneca, and Takeda; support for attending meetings and/or travel from Roche, Takeda, and Pfizer; and advisory abroad from Roche and BMS outside the submitted work. BM reports payment or honoraria from Roche, BMS, MSD, Boehringer Ingelheim, and Pfizer outside the submitted work. SV reports payment or honoraria from Merck GmbH, MSD, BMS, Takeda, AstraZeneca, and Roche; support for attending meetings and/or travel from OSE Immunotherapeutics, Roche, and GMS; and advisory board from Merck GmbH, Puma Biotech, Takeda, Ipsen, AbbVie, Roche, and AstraZeneca outside the submitted work. IBA reports payment or honoraria from AstraZeneca, BMS, Janssen Cilag, Lilly, MSD, Roche, Sanofi, and Takeda; as well as support for attending meetings and/or travel from MSD and AstraZeneca outside the submitted work. JdC reports consulting fees from AstraZeneca, BMS, Roche, MSD, Boehringer Ingelheim, Janssen, Lilly, Sanofi, Takeda, Pfizer, and Glaxo; payment or honoraria from AstraZeneca, BMS, Roche, MSD, Pfizer, Janssen, Takeda, and Sanofi; support for attending meetings and/or travel from AstraZeneca, MSD, and Roche; and advisory Board fees from AstraZeneca, BMS, Roche, MSD, Glaxo, Janssen, and Gilead outside the submitted work. MCo reports consulting fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Lilly, MSD, Takeda, Pfizer, Kyowa, Sanofi, and Janssen, as well as payment or honoraria from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Lilly, MSD, Takeda, Kyowa, Pierre Fabre, Novocure, Sanofi, and Janssen outside the submitted work. JM-L reports payment or honoraria from Roche, BMS, and EUSA Pharma, as well as support for attending meetings and/or travel from Roche outside the submitted work. MP reports consulting fees from BMS, AstraZeneca, MSD, Roche, Takeda. Support for attending meetings and/or travel and payment or honoraria from BMS, AstraZeneca, MSD, Roche, and Takeda outside the submitted work. No disclosures were reported by the other authors., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)