{"doi":"10.1002/ijc.35409","title":"Antitumor efficacy of intermittent low‐dose erlotinib plus sulindac via <scp>MHC</scp> upregulation and remodeling of the immune cell niche","abstract":"Abstract A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon‐γ signaling as a key pathway. In this study, we combine intermittent low‐dose ERL ± SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor‐associated immune modulation. At clinically relevant doses, short‐term (16 weeks) and long‐term (46 weeks) ERL ± SUL administration results in near‐complete tumor suppression in Pirc colon and duodenum ( p &lt; 0.0001). We identify a low‐dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice‐weekly oral gavage (SUL125 + ERL5 × 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL ± SUL upregulates the corresponding MHC and immune‐associated factors in a subset of Pirc colon polyps , Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient‐derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 × 2 increases tumor‐associated Cd4 + T cells by ~2.6‐fold ( p &lt; 0.05), with no apparent effect on Cd8 + T cells. The treatment also increases tumor‐associated Cd68 + cells ( p &lt; 0.05) and decreases Foxp3 + ( p &lt; 0.01) and Arg1 + ( p &lt; 0.05) cells. Thus, intermittent low‐dose ERL + SUL treatment enhances tumor‐associated MHC expression and remodels the immune cell niche toward a more permissive “helper” immune microenvironment. We conclude that early immune‐interception strategies targeting interferon‐γ signaling may benefit FAP patients at drug doses below the clinical standard of care.","journal":"International Journal of Cancer","year":2025,"id":562914,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":778631,"name":"Jorge Enrique Tovar Perez","orcid":"0009-0000-4004-8736","position":1,"is_corresponding":false},{"id":376838,"name":"Sabeeta Kapoor","orcid":"0000-0001-7906-3343","position":2,"is_corresponding":false},{"id":1465319,"name":"Ahmed Muhsin","orcid":"0000-0002-5834-9921","position":3,"is_corresponding":false},{"id":377850,"name":"Wan Mohaiza Dashwood","orcid":null,"position":4,"is_corresponding":false},{"id":1465775,"name":"Yunus Demirhan","orcid":null,"position":5,"is_corresponding":false},{"id":1465320,"name":"Melek Demirhan","orcid":"0009-0002-0161-4461","position":6,"is_corresponding":false},{"id":1465776,"name":"Alessandro Shapiro","orcid":null,"position":7,"is_corresponding":false},{"id":376840,"name":"Altaf Mohammed","orcid":"0000-0003-1058-6909","position":8,"is_corresponding":false},{"id":318557,"name":"Shizuko Sei","orcid":"0000-0002-4822-6602","position":9,"is_corresponding":false},{"id":1465777,"name":"Jacklyn Thompson","orcid":null,"position":10,"is_corresponding":false},{"id":722730,"name":"Mahira Zaheer","orcid":null,"position":11,"is_corresponding":false},{"id":729697,"name":"Krishna M. Sinha","orcid":"0000-0002-7163-7151","position":12,"is_corresponding":false},{"id":292790,"name":"Powel H. Brown","orcid":"0000-0002-3398-163X","position":13,"is_corresponding":false},{"id":376839,"name":"Michelle I. Savage","orcid":"0000-0003-4927-9471","position":14,"is_corresponding":false},{"id":299139,"name":"Eduardo Vilar","orcid":"0000-0001-6404-3761","position":15,"is_corresponding":false},{"id":376836,"name":"Praveen Rajendran","orcid":"0000-0002-6221-7366","position":16,"is_corresponding":false},{"id":291396,"name":"Roderick H. 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