Background: Programmed death ligand-1 (PD-L1), a ligand for PD-1 and B7.1, is broadly expressed on tumor cells (TC) and tumor-infiltrating immune cells (IC) in many human cancers. PD-L1 expression on either TC or IC can negatively regulate antitumor T-cell function within the tumor microenvironment (TME). Consistent with this, the ORR, PFS and OS benefit of atezolizumab (atezo) across PhI and PhII studies appeared to correlate with increasing baseline PD-L1 expression levels on TC and/or IC. Therefore, we explored the biologic reasons for PD-L1 expression on TC and IC, the association with response to atezo and the intrapatient heterogeneity of PD-L1 expression in NSCLC.
Methods: Tumor specimens were obtained from patients (pts) prescreened and/or enrolled in NSCLC atezo trials (PhI PCD4989g, PhII POPLAR and FIR [n=1360]) and from pts treated at MSKCC (n=39). Samples included 14 synchronous and 106 metachronous pairs collected in FIR or at MSKCC. Using the SP142 IHC assay, which has been optimized to detect PD-L1 on both TC and IC, PD-L1 expression was scored at 4 levels (TC0-3 and IC0-3) based on increasing expression. A subset of samples was further characterized by histopathologic review and gene expression by RNAseq. CD8 expression (clone C8/144B) was assessed in the tumor center, invasive margin and periphery by IHC.
Results: PD-L1 was expressed on IC only, on TC only or on both TC and IC within the TME. Tumors with the highest (TC3 or IC3), moderate/high (TC2/3 or IC2/3) and any (TC1/2/3 or IC1/2/3) PD-L1 expression represented ≈15%, ≈38% and ≈70% of NSCLC, respectively. PD-L1 expression was similar across all paired synchronous and metachronous tissues. At the TC3 or IC3 cutoff, PD-L1 status remained unchanged in 86% of paired synchronous specimens and in 78% of metachronous pairs. Analysis of PD-L1 expression patterns revealed the existence of exclusive TC and IC subpopulations at each PD-L1 expression level, unique to NSCLC and not seen in other cancers, e.g. UBC. Strikingly, TC3 and IC3 tumors represented 2 distinct populations, with <1% overlap, each benefiting from atezo. In POPLAR, ORR in TC3 and IC3 subgroups was 40% and 30%, respectively, vs 14.6% in all pts treated with atezo. IC3 tumors had a high frequency of immune infiltrates, including CD8+ T cells, localized in the intra-epithelium, epithelial/stroma interface and stroma. These tumors also exhibited high expression of genes associated with effector T cells, consistent with PD-L1 regulated by an adaptive IFNγ-driven mechanism. However, high infiltration of CD8+ T cells within the tumor at baseline was not associated with response to atezo (P=.39), suggesting that the mechanism of response is not exclusively due to adaptive antitumor T-cell immunity. In contrast, TC3 tumors had distinct histopathologic characteristics, with a dense desmoplastic and sclerotic TME and low intratumoral CD8 infiltrate. PD-L1 on TC appeared to be regulated by intrinsic tumor mechanisms, including promoter methylation. TC0 and IC0 tumors (lowest/no PD-L1 expression; ≈30% of NSCLC) showed little/no evidence of immune infiltration or activation, consistent with immunologic ignorance.
Conclusions: These data demonstrated that NSCLC has unique PD-L1 expression patterns. High expression of PD-L1 on TC and/or IC in NSCLC confers sensitivity to atezo, despite exhibiting distinct immunologic profiles. These results further our understanding of how atezo promotes responses in tumors expressing PD-L1 on TC and/or IC and emphasizes the need to assess PD-L1 on both TC and IC in NSCLC. In addition, intrapatient heterogeneity in PD-L1 expression was relatively low in both synchronous and metachronous tissues, indicating that various types of tumor samples (e.g. primary or metastatic, fresh or archival) can be reliably used to assess PD-L1 expression with the SP142 assay.
Citation Format: Marcin Kowanetz, Hartmut Koeppen, Wei Zou, Sanjeev Mariathasan, Matthew Hellmann, Mark Kockx, Colombe Chappey, Edward Kadel, Dustin Smith, Natasha Miley, Vincent Leveque, Roel Funke, Alan Sandler, Ian McCaffery, Lukas Amler, Daniel Chen, Priti Hegde. PD-L1 as a predictive biomarker for atezolizumab (MPDL3280A; anti-PDL1) in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A017.
- ©2016 American Association for Cancer Research.