Abstract 17P
Background
Tumor mutation burden (TMB) can be a predictor of benefit from treatment with immune checkpoint inhibitors (ICIs); however, some patients whose tumors have high TMBs do not benefit from treatment with ICIs. Loss of beta2-microglobulin (B2M) is a mechanism of acquired resistance to ICIs. We hypothesized that a potential mechanism of inherent resistance to ICIs is the inactivation of B2M and other antigen presenting genes (APGs) resulting from increasing TMBs.
Methods
We identified APGs by expert selection and use of the nferX knowledge synthesis platform. We profiled 9,418 tumors of 33 types in TCGA for somatic mutations and their involvement with APGs. Cohen’s d was used to determine the effect of TMB on mutations in APGs. Whole exome sequencing results from 62 patients with non-small cell lung cancer (NSCLC) treated with nivolumab in second or later lines of therapy were evaluated to determine the effect of mutations in APGs on survival using the log-rank test (Dijon Cohort).
Results
In TCGA, mutations in APGs were associated with increasing TMBs across 33 solid tumors (Cohen’s d=0.731, t-test p=8.476 × 10-199), and specifically in lung adenocarcinoma (n=508, Cohen’s d=0.552, t-test p=8.726 × 10-10). In non-small cell lung cancer (NSCLC) adenocarcinomas, ITGAX and CD1B were some of the most commonly mutated APGs (respectively 8.66%, Cohen’s d=1.132, t-test p-value=5.484 × 10-13; 2.56%, Cohen’s d=1.10, t-test p=2.150 × 10-5). In the Dijon Cohort, there was a mild association of increased TMB with mutations in APGs (Cohen’s d=0.870, t-test p=0.002). Mutations in one or more APGs were associated with improved progression-free survival (PFS; HR=0.54, log rank test p-value=0.04) but not overall survival (HR=0.78, log rank test p=0.49).
Conclusions
Increasing TMBs are strongly associated with mutations in genes essential to antigen presentation, specifically including ITGAX and CD1B in NSCLC. Contrary to our hypothesis, mutations in APGs were associated with improved PFS with nivolumab, possibly due to the involvement of single alleles rather than complete loss. Although bi-allelic loss of APGs may be a mechanism of inherent resistance to ICIs, mutations in these genes may more commonly serve as a surrogate for high TMBs and potential benefit of treatment with PD-1 inhibitors in NSCLC.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J. Park: Full/Part-time employment: nference. F. Ghiringhelli: Honoraria (institution), Oral Communication: Lilly, Sanofi & Amgen; Honoraria (institution), Advisory Board: Merck Serano, Amgen, Sanofi. A.S. Mansfield: Honoraria (institution), Advisory Board: AbbVie; Honoraria (institution), Advisory Board: AstraZeneca; Honoraria (institution), Advisory Board: BMS; Honoraria (institution), Travel/Accommodation/Expenses, Advisory Board: Genentech/Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Verily; Leadership role, Non-Renumerated Director: Mesothelioma Applied Research Foundation. All other authors have declared no conflicts of interest.