| Title: |
Antitumor efficacy of intermittent low‐dose erlotinib plus sulindac via MHC upregulation and remodeling of the immune cell niche |
| Authors: |
Tripathi, Chakrapani; Tovar Perez, Jorge E.; Kapoor, Sabeeta; Muhsin, Ahmed; Dashwood, Wan Mohaiza; Demirhan, Yunus; Demirhan, Melek; Shapiro, Alessandro; Mohammed, Altaf; Sei, Shizuko; Thompson, Jacklyn; Zaheer, Mahira; Sinha, Krishna M.; Brown, Powel H.; Savage, Michelle I.; Vilar, Eduardo; Rajendran, Praveen; Dashwood, Roderick H. |
| Contributors: |
Division of Cancer Prevention, National Cancer Institute |
| Source: |
International Journal of Cancer ; volume 157, issue 2, page 355-370 ; ISSN 0020-7136 1097-0215 |
| Publisher Information: |
Wiley |
| Publication Year: |
2025 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/ijc.35409 |
| Availability: |
https://doi.org/10.1002/ijc.35409; https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.35409 |
| Rights: |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.D7012D45 |
| Database: |
BASE |