Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC

J Thorac Oncol. 2021 Dec;16(12):2078-2090. doi: 10.1016/j.jtho.2021.07.027. Epub 2021 Aug 20.


Introduction: Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression.

Methods: We retrospectively reviewed patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti-PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing.

Results: Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1High (tumor proportion score ≥ 50%)/TILHigh (≥85/mm2; n = 73); type II: PD-L1Low (tumor proportion score < 50%)/TILLow (<85/mm2; n = 70); type III: PD-L1High/TILLow (n = 37); and type IV: PD-L1Low/TILHigh (n = 48). The objective response rate (ORR) and progression-free survival (PFS) of anti-PD-1/PD-L1 therapy clearly differed according to the different TME types (ORR and PFS; type I: 64%, 14.5 mo; type II: 12%, 2.1 mo; type III: 24%, 3.6 mo; type IV; 41%, 10.8 mo). In patients with PD-L1High tumors, type I tumors had significantly better ORR and PFS than type III tumors (ORR: p < 0.001 and PFS: p < 0.001). The presence of TP53 and KRAS mutation was related to the density of CD8-positive TILs and PD-L1 expression, respectively.

Conclusions: Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti-PD-1/PD-L1 therapy.

Keywords: Anti–PD-1/PD-L1 (programmed death-1/programmed death-ligand 1) antibodies; Non–small lung cell cancer (NSCLC); The density of CD8-positive tumor-infiltrating lymphocytes (TILs); Tumor microenvironment (TME).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins
  • B7-H1 Antigen* / antagonists & inhibitors
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Lung Neoplasms* / drug therapy
  • Lymphocytes, Tumor-Infiltrating
  • Retrospective Studies
  • Tumor Microenvironment


  • Apoptosis Regulatory Proteins
  • B7-H1 Antigen
  • Immune Checkpoint Inhibitors