Molecular correlates of immune cytolytic subgroups in colorectal cancer by integrated genomics analysis.

Constantinos Roufas,Ilias Georgakopoulos-Soares,Apostolos Zaravinos

doi:10.1093/narcan/zcab005

Abstract

Although immune checkpoint inhibition (ICI) has shown promising results in metastatic dMMR/MSI-H colorectal cancer (CRC), the majority of pMMR/MSS patients do not respond to such therapies. To systematically evaluate the determinants of immune response in CRC, we explored whether patients with diverse levels of immune cytolytic activity (CYT) have different patterns of chromothripsis and kataegis. Analysis of CRC genomic data from the TCGA, indicated an excess of chromothriptic clusters among CYT-low colon adenocarcinomas, affecting known cancer drivers (APC, KRAS, BRAF, TP53 and FBXW7), immune checkpoints (CD274, PDCD1LG2, IDO1/2 and LAG3) and immune-related genes (ENTPD1, PRF1, NKG7, FAS, GZMA/B/H/K and CD73). CYT-high tumors were characterized by hypermutation, enrichment in APOBEC-associated mutations and kataegis events, as well as APOBEC activation. We also assessed differences in the most prevalent mutational signatures (SBS15, SBS20, SBS54 and DBS2) across cytolytic subgroups. Regarding the composition of immune cells in the tumor milieu, we found enrichment of M1 macrophages, CD8+ T cells and Tregs, as well as higher CD8+ T-cells/Tregs ratio among CYT-high tumors. CYT-high patients had higher immunophenoscores, which is predictive of their responsiveness if they were to be treated with anti-PD-1 alone or in combination with anti-CTLA-4 drugs. These results could have implications for patient responsiveness to immune checkpoint inhibitors.

Highlights

Colorectal cancer (CRC) ranks in the third position of incidence and mortality with ∼1.4 million cases being diagnosed worldwide each year [1]
Our findings reveal that cytolytic activity (CYT)-high tumors are enriched in kataegis, being suggestive of an involvement of the APOBEC cytidine deaminases in the genome of these tumors
To enhance our suggestion that the CYT-high subgroup of CRCs is a previously unappreciated cohort that could benefit from immune checkpoint blockade, we examined the distribution of the tumors across their CYT, tumor mutation burden (TMB) and microsatellite instability (MSI) status, using the Colorectal Adenocarcinoma TCGA PanCancer data

Summary

Introduction

Colorectal cancer (CRC) ranks in the third position of incidence and mortality with ∼1.4 million cases being diagnosed worldwide each year [1]. The remaining 15% of tumors are usually characterized by a defective DNA mismatch repair system (dMMR), due to mutations or epigenetic silencing of MMR genes, such as MSH2 and MLH1 [2,3]. These usually result in microsatellite instability (MSI) and eventually to the accumulation of mutations [4]. The classification for different immunological subtypes in CRC can predict response to immunotherapy and enhance antitumor activity [11,12]. As the TME promotes cancer progression [14], and abnormalities in it can interrupt immunotherapy, its understanding is of major importance in tackling the dis-

Methods

Results

Conclusion