Combinatory analysis of immune cell subsets and tumor-specific genetic variants can predict clinical response to PD-1 blockade for non-small cell lung cancer patients

Abstract

Abstract Blockade of PD-1/PDL1 (PD-1 blockade) with antibodies has revolutionized treatment options for non-small cell lung cancer (NSCLC) patients with tumors without targetable mutations. The benefit of PD-1 blockade is limited only to a subset of the patients. This study aims to identify biological markers of clinical response in a discovery cohort (n=15) of patients early during treatment to distinguish responders from nonresponders using immunological and genetic markers. Immune subsets identified in the blood are characterized to establish a panel of immune markers that could distinguish the two. Blood drawn from NSCLC patients before and after PD-1 blockade was analyzed by clinical flow cytometric assay for changes in the frequencies and concentration of immune cell populations. Next generation sequencing was performed on the extracted DNA from archival tumor biopsies from the same patients. irRECIST criteria was used to evaluate the clinical responses with cut-off at 10 months. Responders had a significantly increased frequency of activated effector memory CD4 & CD8 T cells & decreased frequency of central memory CD4 & CD8 T cells in circulation post-treatment compared to pre-treatment. In a separate cohort we validate initial findings in a cohort of n=29 & observe that effector memory CD8 T cells in responders produced high TNFα at pretreatment. Pathogenic & likely-pathogenic mutations in TP53, KRAS, KEAP1, NOTCH-1 and STK11 in the patients that responded to PD-1 blockade are observed. A multivariate analysis combining immune and genetic parameters could discriminate responders from non-responders. We report that combined analyses of selected immune cell & genetic parameters could predict early clinical response to PD-1 blockade.