Antitumor Efficacy of Intermittent Low-Dose Erlotinib Plus Sulindac via MHC Upregulation and Remodeling of the Immune Cell Niche

Authors

Chakrapani Tripathi
Jorge E Tovar Perez
Sabeeta Kapoor
Ahmed Muhsin
Wan Mohaiza Dashwood
Yunus Demirhan
Melek Demirhan
Alessandro Shapiro
Altaf Mohammed
Shizuko Sei
Jacklyn Thompson
Mahira Zaheer
Krishna M Sinha
Powel H Brown
Michelle I Savage
Eduardo Vilar
Praveen Rajendran
Roderick H Dashwood

Publication Date

7-15-2025

Journal

International Journal of Cancer

DOI

10.1002/ijc.35409

PMID

40072251

PMCID

PMC12079632

PubMedCentral® Posted Date

3-12-2025

PubMedCentral® Full Text Version

Post-print

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 < 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 < 0.05), with no apparent effect on Cd8+ T cells. The treatment also increases tumor-associated Cd68+ cells (p < 0.05) and decreases Foxp3+ (p < 0.01) and Arg1+ (p < 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.

Keywords

Animals, Rats, Erlotinib Hydrochloride, Sulindac, Antineoplastic Combined Chemotherapy Protocols, Male, Adenomatous Polyposis Coli, Up-Regulation, Humans, Tumor Microenvironment, Mice, Female, erlotinib, familial adenomatous polyposis (FAP), MHC, sulindac, tumor immunomodulation

Published Open-Access

yes

Recommended Citation

Tripathi, Chakrapani; Tovar Perez, Jorge E; Kapoor, Sabeeta; et al., "Antitumor Efficacy of Intermittent Low-Dose Erlotinib Plus Sulindac via MHC Upregulation and Remodeling of the Immune Cell Niche" (2025). Faculty, Staff and Student Publications. 4272.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4272