Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC

Introduction: According to mechanisms of adaptive im-mune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)-negative and tumor-infiltrating lymphocyte (TIL)- negative (type I); (2) PD-L1-positive and TIL-positive (type II); (3) PD-L1-negative and TIL-positive (type III); and (4) PD-L1-positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among pa-tients with advanced NSCLC. Methods: On the basis of RNA-sequencing and immuno-histochemistry data from the ORIENT-11 study, we opti-mized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy. Results: PD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemo-therapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06-0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13-0.55, p < 0.001). In the combi-nation group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were suscep-tible to having similar PFS. In the chemotherapy group, there was no marked association between survival out-comes and TIME subtypes. Conclusions: Only patients with both high PD-L1 expres-sion and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens. & COPY; 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).