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

Ricardo E. Vilain, Alexander M. Menzies, James S. Wilmott, Hojabr Kakavand, Jason Madore, Alexander Guminski, Elizabeth Liniker, Benjamin Y. Kong, Adam J. Cooper, Julie R. Howle, Robyn P.M. Saw, Valerie Jakrot, Serigne Lo, John F. Thompson, Matteo S. Carlino, Richard F. Kefford, Georgina V. Long, Richard A. Scolyer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)

Abstract

Purpose: Disruption of PD-L1/cytotoxic T-cell PD-1 signaling 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-PD-1 therapies in patients with melanoma, particularly early during treatment, and correlate them with treatment response. Experimental Design: Forty-six tumor biopsies from 23 patients with unresectable AJCC stage III/IV melanoma receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, n = 21), within 2 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), and 10 did not respond. Results: PRE intratumoral and peritumoral PD-1+ T-cell densities were sevenfold (P = 0.006) and fivefold higher (P = 0.011), respectively, in responders compared with nonresponders 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 was not significantly different between the patient groups, but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders versus nonresponders (P= 0.025 and P= 0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intratumoral CD8+ lymphocytes (P = 0.046) and intratumoral CD68+ macrophages (P = 0.046). 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-PD-1 therapies and warrants further evaluation.

Original languageEnglish
Pages (from-to)5024-5033
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number17
DOIs
Publication statusPublished - 1 Sep 2017
Externally publishedYes

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