A Variant of a Killer Cell Immunoglobulin-like Receptor is Associated with Resistance to PD-1 Blockade in Lung Cancer

Purpose: PD-(L)1 blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade.Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. Experimental Design: Peripheral blood mononuclear cells were collected from 35 NSCLC patients receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and non-responders to treatment. Findings were confirmed in additional cohorts of NSCLC patients receiving immune checkpoint blockade. Results: We identified a genetic variant of a Killer Cell Immunoglobulin-like Receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in NSCLC patients. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR 1.72, 95 % CI 1.10 to 2.68, P=0.017). No relationship was seen in cohorts of NSCLC patients who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be to NK cell reactivity. Conclusions:We identify an association of the KIR3DS1 allelic variant with response to PD-1 targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. While the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive marker for response to PD-1 immunotherapy.