Abstract: Tumor mutation burden (TMB) is used to select patients to receive immune checkpoint inhibitors (ICIs) but has mixed predictive capabilities. We hypothesized that inactivation of antigen presenting genes (APGs) that result from increased TMBs would result in inherent resistance to ICIs. We observed that somatic mutations in APGs were associated with increasing TMBs across 9,418 tumors of 33 different types. In adenocarcinomas of the lung, ITGAX and CD1B were some of the most commonly mutated APGs. In 62 patients with non-small cell lung cancers treated with a PD-1 inhibitor in second or later lines of therapy, there was an association of increased TMB with mutations in APGs; however, mutations in one or more APGs were associated with improved progression-free survival. Contrary to our hypothesis, mutations in APGs were associated with improved progression-free survival with nivolumab, possibly due to the involvement of single alleles rather than complete loss.
Enrique M. Garcia-Rivera, Jiho Park, Aakash Desai, Romain Boidot, Sandy Chevrier, Caroline Truntzer, Francois Ghiringhelli, Mitesh Borad, Aaron S. Mansfield