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

Emil Lou; Joanne Xiu; Yasmine Baca; Anwaar Saeed; Ajay Prakash; Sepideh Gholami; Subbaya Subramanian; Timothy K Starr; Elisa Fontana; Ritu Pandey; Heinz-Josef Lenz; Anthony F Shields; Chadi Nabhan; Matthew Oberley; Andreas Seeber; Wafik El-Deiry

doi:10.1016/j.omton.2024.200786

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

Mol Ther Oncol. 2024 Feb 28;32(1):200786. doi: 10.1016/j.omton.2024.200786. eCollection 2024 Mar 21.

Authors

Affiliations

¹ Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
² Caris Life Sciences, Phoenix, AZ, USA.
³ University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁴ Northwell Health, New Hyde Park, NY, USA.
⁵ Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
⁶ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN, USA.
⁷ Drug Development Unit, Sarah Cannon Research Institute UK, Marylebone, London, UK.
⁸ Arizona Cancer Center, Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
⁹ Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁰ Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
¹¹ Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
¹² Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Legorreta Cancer Center, Brown University, Providence, RI, USA.

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.

Keywords: KRAS; MT: Regular Issue; RAS; colorectal cancer; early-onset colorectal cancer; immune infiltration; immunoevasion; next-generation sequencing; tumor immune microenvironment; tumor microenvironment; young-adult colorectal cancer.