KIR Polymorphism is Associated with Primary Resistance to PD-1 Blockade in Lung Cancer

Adaptive immune escape of tumor cells by upregulation of ligands for programmed death 1 (PD-1) has been identified as an important and targetable pathway in many cancer types. Many clinical trials have demonstrated that targeting PD-1 or its ligand PD-L1 with immune checkpoint inhibitors (ICI) can restore anti-tumor immunity and induce durable remission. In patients with non-small cell lung cancer (NSCLC), several trials have demonstrated a survival benefit with ICI in patients with metastatic and locally advanced NSCLC.Yet, most patients have primary resistance to PD-1 or PD-L1 blockade during treatment: approximately 20% of unselected patients with NSCLC achieve a partial response while 40-50% have progressive disease as best response. Understanding mechanisms of primary resistance to PD-(L)1 blockade is important in the search for potentially targetable pathways and may ultimately allow discrimination between patients that benefit from PD-(L)1 blockade and those requiring combination or other approaches. We collected PBMCs and serum samples from 35 patients with NSCLC before and during PD-1 blockade treatment with nivolumab. We analyzed differentially expressed genes in CD8+ T cells from the peripheral blood of 5 patients with partial response and 5 patients with primary progressive disease to identify mechanisms of resistance to PD-1 therapy. Cells were collected from samples taken before and after 4 weeks of treatment. Peripheral blood mononuclear cells (PBMCs) were prospectively collected from metastatic NSCLC patients (discovery cohort) just before the first administration (N1) and during treatment (at 4 weeks, N2) with PD-1 blockade. Patiens were classified to either "responder"(partial response PR) or "nonresponder" (progressive disease PD) based on objective radiological response by RECIST by a thoraic radiologist. From 5 responder and 5 nonresponder patients peripheral CD8+ T cells were sorted by fluorescence activated cell sorting using a BD FACS AriaIII and RNA isolated from these cells. We investigated changes in RNA expression upon treatment wit PD-1 blockade associated with clinical response.