TY - JOUR
T1 - Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in Melanoma
AU - Vilain, Ricardo E.
AU - Menzies, Alexander M.
AU - Wilmott, James S.
AU - Kakavand, Hojabr
AU - Madore, Jason
AU - Guminski, Alexander
AU - Liniker, Elizabeth
AU - Kong, Benjamin Y.
AU - Cooper, Adam J.
AU - Howle, Julie R.
AU - Saw, Robyn P. M.
AU - Jakrot, Valerie
AU - Lo, Serigne
AU - Thompson, John F.
AU - Carlino, Matteo S.
AU - Kefford, Richard F.
AU - Long, Georgina V.
AU - Scolyer, Richard A.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029539217&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-0698
DO - 10.1158/1078-0432.CCR-16-0698
M3 - Article
C2 - 28512174
AN - SCOPUS:85029539217
SN - 1078-0432
VL - 23
SP - 5024
EP - 5033
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -