Regulation of MHC Class II expression in colorectal cancer

Pickles, Oliver James ORCID: 0000-0002-8519-7644 (2021). Regulation of MHC Class II expression in colorectal cancer. University of Birmingham. Ph.D.

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Abstract

The vast majority of colorectal cancers (CRC) fail to respond to immune checkpoint blockade (ICB). Tumour MHC Class II expression correlates with improved response to ICB and survival in other cancers. Most pMMR CRC does not express Class II and half of CRC cell lines exhibit promoter methylation of the Class II transactivator (CIITA).

A collection of fifteen CRC organoids was established, eight were found to be strongly-inducible for Class II after 24 hours. Of the remaining tumours, 3 were Class II non-inducible and were deficient in IFNγ signalling and four displayed only weak Class II expression. CIITA methylation was not found in any organoids, in contrast to cell lines. Class II expression correlated with CIITA mRNA expression and ChIP PCR confirmed CIITA promoter histone acetylation in responsive lines, histone methylation was again not observed. Weakly-inducible lines had evidence of EZH2 occupancy of CIITA, however, most could strongly express Class II with prolonged IFNγ exposure for 72 hours, with responses further enhanced with EZH2 inhibition.

Deficiency of activated T cells within the CRC microenvironment is likely to explain the absence of Class II expression in many tumours. Organoids should be the standard tissue culture method for assessing epigenetics in cancer.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):