Microbial induction of MHC-II expression in colon cancer cells overcomes immunotherapy resistance and limits metastasis

Chung, Charlie, Ozcelik, Elif, Zhang, Jialing, Shen, Zeli, Eskiocak, Onur, Qin, Yihan, Habel, Jill, Ozler, Kadir, Subhash, Santhilal, Aminzada, Zakaria, Dev, Gagan, Garcia, Libia, Lyons, Scott K, Hand, Timothy W, Rivadeneira, David E, Fox, James G, Westcott, Peter MK, Rogava, Meri, Beyaz, Semir (July 2026) Microbial induction of MHC-II expression in colon cancer cells overcomes immunotherapy resistance and limits metastasis. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Colorectal cancer remains a major cause of cancer mortality, and most microsatellite stable tumors derive little benefit from immune checkpoint blockade. Here, we identify a microbiome-dependent mechanism that converts immune-refractory colorectal cancer into a more immunologically responsive state. Using orthotopic mouse models spanning distinct genetic and immunologic contexts, we show that a Helicobacter-containing microbiome suppresses primary tumor growth and limits metastasis. This protective state is associated with increased intratumoral lymphocyte infiltration and stronger effector programs. Mechanistically, microbial exposure induces MHC class II expression in colon cancer cells to promote anti-tumor immunity. Tumor-intrinsic loss of CIITA abrogates microbial protection, whereas enforced CIITA expression is sufficient to increase intratumoral T cell accumulation, restrict progression and metastasis, and sensitize microsatellite-stable tumors to PD-1 and CTLA-4 blockade. In human microsatellite-stable patient-derived organoids, increased cancer-cell MHC-II enhanced interactions with autologous immune cells and increased tumor cell apoptosis. Together, these findings define a microbiome-cancer cell antigen presentation axis that restrains metastasis and overcomes immunotherapy resistance in colorectal cancer.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > major histocompatibility complex diseases & disorders > cancer > metastasis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:	Chung, Charlie Eskiocak, Onur Habel, Jill Ozler, Kadir Subhash, Santhilal Garcia, Libia Lyons, Scott Westcott, Peter Beyaz, Semir Zhang, Jialin Qin, Yihan Aminzada, Zakeria
Communities:	CSHL labs > Beyaz lab CSHL labs > Lyons lab CSHL Post Doctoral Fellows School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	4 July 2026
Date Deposited:	22 Jul 2026 18:41
Last Modified:	22 Jul 2026 18:41
PMCID:	PMC13345130
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42274

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