Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma.

Abstract

Disruption of PD-L1/cytotoxic T-cell PD-1 signalling by immune-checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD1 therapies in melanoma patients, particularly early during treatment, and correlate them with treatment response<br /><br />Experimental Design: Forty-six tumor biopsies from 23 unresectable AJCC Stage III/IV melanoma patients receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, n=21), within two months of commencing treatment (EDT, n=20) and on disease progression after previous response (PROG, n=5). Thirteen patients responded (defined as CR, PR or durable SD by RECIST/irRC criteria), ten didn't respond. <br /><br />Results: PRE intra-tumoral and peri-tumoral PD-1+ T-cells density were 7-fold (p=0.006) and 5-fold higher (p=0.011), respectively in responders compared with non-responders and correlated with degree of radiologic tumor response (r=-0.729, p=0.001 and r=-0.725, p=0.001, respectively). PRE PD-L1 expression on tumor and macrophages wasn't significantly different between the patient groups but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders vs. non-responders (p=0.025 and p=0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intra-tumoral CD8+ lymphocytes (p=0.046) and intratumoral CD68+ macrophages (p=0.046).<br /><br />Conclusions: Higher PRE PD-1+ T-cells in responders suggest active suppression of an engaged immune system that is disinhibited by anti-PD-1 therapies. Furthermore, immunoprofiling of EDT biopsies for increased PD-L1 expression and immune cell infiltration showed greater predictive utility than PRE biopsies, and may allow better selection of patients most likely to benefit from anti-PD1 therapies and warrants further evaluation.