Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer

Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/βCatenin, mitogen-activated protein kinase and TGFβ receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression. ### Competing Interest Statement MG receives research funding from Merck KG and Bristol Myers Squibb. DC receives research funding from Astra Zeneca, Clovis, Eli Lilly, 4SC, Bayer, Celegene and Roche and is on the advisor board of OVIBIO. DL is the recipient of the Australasian Gastro-Intestinal Trials Group/Merck Clinical Research Fellowship. NM is on the advisory board for BMS, Novartis, Pfizer and Roche and the Speakers’ bureau for Merck, Pfizer and Roche. JR-B receives travel and accommodation expenses from Bristol-Myers Squibb, Merck Sharp & Dohme, Ipsen, PharmaMar and Roche; honoraria for educational activities from Pfizer and Roche; honoraria for consultancy from Boehringer Ingelheim; and institutional research funding from Roche. KS receives travel, accommodation, national/international meetings registration and consultancy renumeration from BMS, Daiichi-Sankyo, Guardant Health, Innovent Biologics, Merck KG, Mirati Therapeutics, MSD, Roche, Servier; and Institutional funding for trials and research at UCLH from Adaptimmune Therapeutics, BMS, Merck KGaA, MSD, Roche.