The effectiveness of KRAS G12C inhibition as a cancer treatment was recently reported. Knowing the association between RAS mutation and the expression level of immune checkpoint markers is of interest since it may guide a potential combination therapy of RAS inhibition and immune checkpoint blockade.
498 patients with various types of solid tumors were included in the analysis. The RNA expression levels of immune checkpoint markers in these patients’ samples were measured by RNA sequencing, normalized by internal housekeeping gene profiles, and ranked from 0 to 100th percentile against a pan-cancer reference population of 735 tumors. “High” expression was defined as expression rank ≥75th percentile. Genomic variants in the tumor samples and/or serum cell-free DNA (cfDNA) were analyzed with next-generation sequencing and the mutational status of the RAS gene family (KRAS, NRAS, and HRAS) were summarized.
The most common types of cancer in the cohort were colorectal and pancreatic cancer. (27.7% and 10.8%, respectively). 163 patients (32.7%) harbored RAS mutation or amplification in the tumor or serum cfDNA. The most common RAS mutations were KRAS G12D and G12V. (27.6% and 19.0%, respectively) RAS-mutant patients had a significantly larger proportion of high NOS2 expression compared to RAS-wild type patients (35.0% vs 17.0%, p < 0.001). In contrast, RAS-wild type patients had a significantly larger proportion of VTCN1 (B7-H4) high expression compared to RAS-mutant patients. (23.3% vs 8.0%, p < 0.001). After adjusting for tumor type, sex, and age, a significant inverse association between high VTCN1 expression and RAS-mutant status was seen (p = 0.012). No other checkpoint markers including PD-1, PD-L1, CTLA4 or LAG3, showed significant association with RAS status.
Patients with RAS mutations are less likely to have high expression of VTCN1. VTCN1 is a co-inhibitory molecule which negatively regulates T-cell immune response and promotes immune escape. The association between genetic mutations in cancer cells and the immune status in the tumor microenvironment may suggest potential treatment with combination targeted therapy plus immunotherapy.
Clinical trial identification
Legal entity responsible for the study
This study was funded in part by the Joan and Irwin Jacobs Fund and NIH P30 CA023100.
R. Kurzrock: Financial Interests, Invited Speaker: Biological Dynamics, Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, TopAlliance, Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Biological Dynamics, Eisai, EOM Pharmaceuticals, Iylon, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech, CureMatch Inc, CureMetrix, IDbyDNA. S. Pabla: Financial Interests, Stocks/Shares: Omniseq. M. Nesline: Financial Interests, Stocks/Shares: Omniseq. S. Glenn: Financial Interests, Stocks/Shares: Omniseq. J. Conroy: Financial Interests, Stocks/Shares: Omniseq. P. DePietro: Financial Interests, Stocks/Shares: Omniseq. S. Kato: Financial Interests, Invited Speaker: Foundation Medicine, NeoGenomics, CureMatch, Roche, Pfizer, ACT Genomics, Sysmex, Konica Minolta, OmniSeq. All other authors have declared no conflicts of interest.