Differential landscape of immune evasion in oncogenic RAS-driven primary and metastatic colorectal cancers

Lou, Emil, Xiu, Joanne, Baca, Yasmine, Saeed, Anwaar, Prakash, Ajay, Gholami, Sepideh, Subramanian, Subbaya, Starr, Timothy K, Fontana, Elisa, Pandey, Ritu, Lenz, Heinz-Josef, Shields, Anthony F, Nabhan, Chadi, Oberley, Matthew, Seeber, Andreas, El-Deiry, Wafik (March 2024) Differential landscape of immune evasion in oncogenic RAS-driven primary and metastatic colorectal cancers. Mol Ther Oncol, 32 (1). p. 200786. ISSN 2950-3299

PDF 1-s2.0-S2950329924000286-main.pdf - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (3MB)

Abstract

Oncogenic drivers such as KRAS extensively modulate the tumor inflammatory microenvironment (TIME) of colorectal cancer (CRC). The influence of KRAS on modulating immune cell composition remains unclear. The objective of this study was to identify signatures of infiltrative immune cells and distinctive patterns that differ between RAS wild-type (WT) and oncogenic mutant (MT) CRC that explain immune evasion in MT tumors. A total of 7,801 CRC specimens were analyzed using next-generation DNA sequencing, whole-exome sequencing, and/or whole transcriptome sequencing. Deficiency of mismatch repair (dMMR)/microsatellite instability (MSI) and tumor mutation burden (TMB) were also assessed. KRAS mutations were present in 48% of CRC, similarly distributed in patients younger than vs. 50 years and older. In microsatellite stable (MSS) KRAS MT tumors, composition of the TIME included higher neutrophil infiltration and lower infiltration of B cells. MSI-H/dMMR was significantly more prevalent in RAS WT (9.1%) than in KRAS MT (2.9%) CRC. In MSS CRC, TMB-high cases were significantly higher in RAS MT (3.1%) than in RAS WT (2.1%) tumors. KRAS and NRAS mutations are associated with increased neutrophil infiltration, with codon-specific differences. These results demonstrate significant differences in the TIME of RAS mutant CRC that match previous reports of immunoevasive characteristics of such tumors.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > colon cancer diseases & disorders > cancer > cancer types > colon cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Gholami, Sepideh
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Gholami Lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	21 March 2024
Date Deposited:	12 Apr 2024 20:08
Last Modified:	12 Apr 2024 20:08
PMCID:	PMC10963927
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41512

Actions (login required)

Administrator's edit/view item