MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids
Author
Pickles, Oliver JWanigasooriya, Kasun
Ptasinska, Anetta
Patel, Akshay J
Robbins, Helen L
Bryer, Claire
Whalley, Celina M
Tee, Louise
Lal, Neeraj
Pinna, Claudia M A
Elzefzafy, Nahla
Taniere, Philippe
Beggs, Andrew D
Middleton, Gary M
Publication date
2023-08-09
Metadata
Show full item recordAbstract
Tumor-specific MHC class II (tsMHC-II) expression impacts tumor microenvironmental immunity. tsMHC-II positive cancer cells may act as surrogate antigen-presenting cells and targets for CD4+ T cell-mediated lysis. In colorectal cancer, tsMHC-II negativity is common, in cell lines due to CIITA promoter methylation. To clarify mechanisms of tsMHC-II repression in colorectal cancer, we analyzed colorectal cancer organoids which are epigenetically faithful to tissue of origin. 15 primary colorectal cancer organoids were treated with IFNγ ± epigenetic modifiers: flow cytometry was used for tsMHC-II expression. qRT-PCR, total RNA sequencing, nanopore sequencing, bisulfite conversion/pyrosequencing, and Western blotting was used to quantitate CIITA, STAT1, IRF1, and JAK1 expression, mutations and promoter methylation and chromatin immunoprecipitation to quantitate H3K9ac, H3K9Me2, and EZH2 occupancy at CIITA. We define three types of response to IFNγ in colorectal cancer: strong, weak, and noninducibility. Delayed and restricted expression even with prolonged IFNγ exposure was due to IFNγ-mediated EZH2 occupancy at CIITA. tsMHC-II expression was enhanced by EZH2 and histone deacetylase inhibition in the weakly inducible organoids. Noninducibility is seen in three consensus molecular subtype 1 (CMS1) organoids due to JAK1 mutation. No organoid demonstrates CIITA promoter methylation. Providing IFNγ signaling is intact, most colorectal cancer organoids are class II inducible. Upregulation of tsMHC-II through targeted epigenetic therapy is seen in one of fifteen organoids. Our approach can serve as a blueprint for investigating the heterogeneity of specific epigenetic mechanisms of immune suppression across individual patients in other cancers and how these might be targeted to inform the conduct of future trials of epigenetic therapies as immune adjuvants more strategically in cancer. Significance: Cancer cell expression of MHC class II significantly impacts tumor microenvironmental immunity. Previous studies investigating mechanisms of repression of IFNγ-inducible class II expression using cell lines demonstrate epigenetic silencing of IFN pathway genes as a frequent immune evasion strategy. Unlike cell lines, patient-derived organoids maintain epigenetic fidelity to tissue of origin. In the first such study, we analyze patterns, dynamics, and epigenetic control of IFNγ-induced class II expression in a series of colorectal cancer organoids.Citation
Pickles OJ, Wanigasooriya K, Ptasinska A, Patel AJ, Robbins HL, Bryer C, Whalley CM, Tee L, Lal N, Pinna CMA, Elzefzafy N, Taniere P, Beggs AD, Middleton GM. MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids. Cancer Res Commun. 2023 Aug 9;3(8):1501-1513. doi: 10.1158/2767-9764.CRC-23-0091. PMID: 37565053; PMCID: PMC10411481.Type
ArticleAdditional Links
https://crc.aacrjournals.org/cancerrescommunPMID
37565053Journal
Cancer Research CommunicationsPublisher
American Association for Cancer Researchae974a485f413a2113503eed53cd6c53
10.1158/2767-9764.CRC-23-0091