{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:40:52Z","timestamp":1784691652584,"version":"3.55.0"},"reference-count":28,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Anti-programmed death 1 receptor (PD-1) therapy is a promising treatment strategy for patients with unresectable advanced or recurrent gastric\/gastroesophageal junction (G\/GEJ) cancer. However, its response rate and survival benefits are still limited; an immunological analysis of the residual tumor after anti-PD-1 therapy would be important. Methods: We evaluated the clinical efficacy of tumor resection (TR) after chemotherapy or anti-PD-1 therapy in patients with unresectable advanced or recurrent G\/GEJ cancer and analyzed the immune status of tumor microenvironment (TME) by immunohistochemistry using their surgically resected specimens. Results: Patients treated with TR after anti-PD-1 therapy had significantly longer survival compared to those treated with chemotherapy and anti-PD-1 therapy alone. Expression of human leukocyte antigen (HLA) class I and major histocompatibility complex (MHC) class II on tumor cells was markedly downregulated after anti-PD-1 therapy compared to chemotherapy. Furthermore, the downregulation of HLA class I may be associated with the activation of transforming growth factor-\u03b2 signaling pathway in the TME. Conclusions: Immune escape from cytotoxic T lymphocytes may be induced in the TME in patients with unresectable advanced or recurrent G\/GEJ cancer after anti-PD-1 therapy due to the downregulation of HLA class I and MHC class II expression on tumor cells. TR may be a promising treatment strategy for these patients when TR is feasible after anti-PD-1 therapy.<\/jats:p>","DOI":"10.3390\/cells14151212","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T15:09:53Z","timestamp":1754492993000},"page":"1212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Residual Tumor Resection After Anti-PD-1 Therapy: A Promising Treatment Strategy for Overcoming Immune Evasive Phenotype Induced by Anti-PD-1 Therapy in Gastric Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Hajime","family":"Matsuida","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2565-154X","authenticated-orcid":false,"given":"Kosaku","family":"Mimura","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"},{"name":"Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuharu","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohei","family":"Hayashishita","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Takiguchi","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azuma","family":"Nirei","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Hanayama","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-4746","authenticated-orcid":false,"given":"Hirokazu","family":"Okayama","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-3520","authenticated-orcid":false,"given":"Motonobu","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Momma","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zenichiro","family":"Saze","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kono","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0140-6736(21)00797-2","article-title":"First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial","volume":"398","author":"Janjigian","year":"2021","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S1470-2045(21)00692-6","article-title":"Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): A randomised, multicentre, double-blind, placebo-controlled, phase 3 trial","volume":"23","author":"Kang","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/S1470-2045(23)00515-6","article-title":"Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): A multicentre, randomised, double-blind, phase 3 trial","volume":"24","author":"Rha","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1038\/s41591-023-02465-7","article-title":"Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: The randomized, phase 3 GLOW trial","volume":"29","author":"Shah","year":"2023","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/S0140-6736(23)00620-7","article-title":"Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): A multicentre, randomised, double-blind, phase 3 trial","volume":"401","author":"Shitara","year":"2023","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s10120-015-0575-z","article-title":"Is conversion therapy possible in stage IV gastric cancer: The proposal of new biological categories of classification","volume":"19","author":"Yoshida","year":"2016","journal-title":"Gastric Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Choe, H.J., Kim, J.W., Han, S.H., Lee, J.H., Ahn, S.H., Park, D.J., Kim, J.W., Kim, Y.J., Lee, H.S., and Kim, J.H. (2019). Conversion Surgery in Metastatic Gastric Cancer and Cancer Dormancy as a Prognostic Biomarker. Cancers, 12.","DOI":"10.3390\/cancers12010086"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1007\/s00432-021-03516-7","article-title":"Survival benefit of conversion surgery after intensive chemotherapy for unresectable metastatic gastric cancer: A propensity score-matching analysis","volume":"147","author":"Ohnuma","year":"2021","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/ags3.12515","article-title":"International Retrospective Cohort Study of Conversion Therapy for Stage IV Gastric Cancer 1 (CONVO-GC-1)","volume":"6","author":"Yoshida","year":"2022","journal-title":"Ann. Gastroenterol. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1038\/s41467-020-15726-7","article-title":"Transcriptional downregulation of MHC class I and melanoma de-differentiation in resistance to PD-1 inhibition","volume":"11","author":"Lee","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1007\/s00262-022-03154-z","article-title":"Immune escape mechanism behind resistance to anti-PD-1 therapy in gastrointestinal tract metastasis in malignant melanoma patients with multiple metastases","volume":"71","author":"Ito","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1158\/1541-7786.MCR-20-0308","article-title":"A TGFbeta-Dependent Stromal Subset Underlies Immune Checkpoint Inhibitor Efficacy in DNA Mismatch Repair-Deficient\/Microsatellite Instability-High Colorectal Cancer","volume":"18","author":"Endo","year":"2020","journal-title":"Mol. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.immuni.2016.05.001","article-title":"Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation","volume":"44","author":"Anderson","year":"2016","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s10120-020-01151-8","article-title":"Combined inhibition of PD-1\/PD-L1, Lag-3, and Tim-3 axes augments antitumor immunity in gastric cancer-T cell coculture models","volume":"24","author":"Mimura","year":"2021","journal-title":"Gastric Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"200ra116","DOI":"10.1126\/scitranslmed.3006504","article-title":"Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8+ T cells","volume":"5","author":"Spranger","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1111\/cas.12938","article-title":"Negative influence of programmed death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy","volume":"107","author":"Tanaka","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1111\/cas.14336","article-title":"Cisplatin-induced programmed cell death ligand-2 expression is associated with metastasis ability in oral squamous cell carcinoma","volume":"111","author":"Sudo","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1158\/1078-0432.CCR-18-3200","article-title":"Biological Consequences of MHC-II Expression by Tumor Cells in Cancer","volume":"25","author":"Axelrod","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.4049\/jimmunol.1900778","article-title":"Cancer Cell-Intrinsic Expression of MHC Class II Regulates the Immune Microenvironment and Response to Anti-PD-1 Therapy in Lung Adenocarcinoma","volume":"204","author":"Johnson","year":"2020","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/nature13848","article-title":"CEACAM1 regulates TIM-3-mediated tolerance and exhaustion","volume":"517","author":"Huang","year":"2015","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wang, D., Gu, Y., Yan, X., Huo, C., Wang, G., Zhao, Y., Teng, M., and Li, Y. (2022). Role of CD155\/TIGIT in Digestive Cancers: Promising Cancer Target for Immunotherapy. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.844260"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nri3700","article-title":"Ectopic lymphoid-like structures in infection, cancer and autoimmunity","volume":"14","author":"Pitzalis","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era of cancer immunotherapy","volume":"19","author":"Petitprez","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e157215","DOI":"10.1172\/jci.insight.157215","article-title":"CXCL13-producing CD4+ T cells accumulate in the early phase of tertiary lymphoid structures in ovarian cancer","volume":"7","author":"Ukita","year":"2022","journal-title":"JCI Insight"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9023","DOI":"10.1245\/s10434-024-16161-4","article-title":"Conversion Surgery After Chemotherapy Plus Nivolumab as the First-Line Treatment for Unresectable Advanced or Recurrent Gastric Cancer and a Biomarker Study Using the Gustave Roussy Immune Score: A Multicenter Study","volume":"31","author":"Nakazawa","year":"2024","journal-title":"Ann. Surg. Oncol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1212\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:24:53Z","timestamp":1760034293000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":28,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cells14151212"],"URL":"https:\/\/doi.org\/10.3390\/cells14151212","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,6]]}}}