Many studies have focused on the role of programmed death receptor ligand 1 (PD-L1) expression in predicting immunotherapy outcomes. Limited clinical data are available regarding the role of programmed death receptor 1 (PD-1; the PD-L1 receptor) expressing tumor-infiltrating lymphocytes (TILs) in PD-1/PD-L1 antibody responsiveness. However, preclinical studies demonstrate that TILs expressing PD-1 contribute to tumor immune evasion.
This study analyzed the association between TIL-PD-1 status and outcome after immune checkpoint blockade (ICB) therapy. We evaluated 123 patients with various solid tumors treated with monoclonal antibodies targeting the PD-1/PD-L1 signaling axis. Additionally, 8706 solid tumor specimens were assessed for TIL-PD-1 and tumor mutational burden (TMB) status.
The presence of PD-1-expressing TILs in tumors was associated with increased median progression-free survival (7.0 vs 1.9 months; p = 0.006) and overall survival (18.1 vs 8.0 months; p = 0.04) after treatment with ICB. TIL-PD-1–positive patients had an objective response rate (ORR) of 41% (95% CI, 24–61; N = 12/29) compared with 17% (95% CI, 4–43; N = 3/17) for TIL-PD-1–negative patients (p = 0.18). Analyzed as continuous variables, TIL-PD-1 and TMB showed a weak correlation in 8706 solid tumor samples (Pearson r = 0.074); when analyzed as categorical variables (cutoffs: TIL-PD-1 ≥ 1% and TMB ≥ 10 mutations/Mb), the two variables are correlated (p < 0.0001). TIL-PD-1–positive status is also associated with enrichment of pathologic variants within several genes, most notably TP53 (adjusted p < 0.05).
TIL-PD-1 positivity in tumors (≥ 1%) is associated with significantly longer progression-free and overall survival after ICB. ClinicalTrials.gov ID: NCT02478931
Source of Support: Funded in part by National Cancer Institute Grant P30 CA023100 and the Joan and Irwin Jacobs Fund philanthropic fund.
Conflict of interest: Nicholas Bevins receives speaker fees from Thermo-Fisher Scientific. Meagan Montesion is an employee of Foundation Medicine, Inc. and holds equity interest in Roche holding AG. Aaron Goodman receives consulting fees from EUSA Pharma and Seattle Genetics. Razelle Kurzrock reports research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant; consultant, speaker, and/or advisory board role for X-Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics, Inc.; equity interest in IDby DNA and CureMatch Inc.; Board member of CureMatch and CureMetrix; and a cofounder of CureMatch. The remaining authors have no conflicts of interest.