Conventional therapy induces tumor immunoediting and modulates the immune contexture in colorectal cancer

Abstract

BackgroundCancer immunotherapies for patients with colorectal cancer (CRC) continue to lag behind other solid cancer types with the exception of 4% of patients with microsatellite-instable tumors. Thus, there is an urgent need to broaden the clinical benefit of checkpoint blockers to CRC by combining conventional therapies to sensitise tumors to immunotherapy. However, the impact of conventional drugs on immunoediting, potentially promoting the positive selection of less immunogenic variants, and on the tumor immune contexture in CRC, remain elusive. MethodsWe performed comprehensive multimodal profiling using longitudinal samples from metastatic CRC patients undergoing neoadjuvant therapy with mFOLFOX6 and Bevacizumab. Exome-sequencing, RNA-sequencing and multiplexed immunofluorescence imaging was carried out on tumor samples obtained before and after therapy and the data was analysed using established methods. The results of the analysis were extrapolated to publicly available datasets (TCGA and CPTAC). In order to identify a surrogate marker, an explainable artificial intelligence method was developed using a transformer-based analytical pipeline for the identification of features in Hematoxylin and Eosin (H&E) images associated with specific biological processes, followed by manual evaluation of highly informative tiles by a pathologist. ResultsMutational profiles were highly modified and the level of genetic intertumoral heterogeneity between patients varied following treatment. Evolutionary analysis indicated eradication of some clones and dominant clonal prevalence of others, supporting the notion of pharmacologically-induced cancer immunoeditin. Post treatment samples showed upregulation of HLA class II genes, activation of differentiation and stemness pathways, and changes in the consensus molecular subtypes. The tumor immune contexture was characterised by increased densities of CD8+ and CD4+ T cells, but reduced T cell-tumor cell interactions (and increased T cell exhaustion. The AI-guided analyses of the H&E images pinpointed extracellular mucin deposits associated with stemness genes, suggesting a surrogate marker for routine pathological evaluation. ConclusionsConventional therapy induces immunoediting and modulates the immune contexture in metastatic CRC patients.