Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC. 2021

Masayuki Shirasawa, and Tatsuya Yoshida, and Yukiko Shimoda, and Daisuke Takayanagi, and Kouya Shiraishi, and Takashi Kubo, and Sachiyo Mitani, and Yuji Matsumoto, and Ken Masuda, and Yuki Shinno, and Yusuke Okuma, and Yasushi Goto, and Hidehito Horinouchi, and Hitoshi Ichikawa, and Takashi Kohno, and Noboru Yamamoto, and Shingo Matsumoto, and Koichi Goto, and Shun-Ichi Watanabe, and Yuichiro Ohe, and Noriko Motoi
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

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

UI MeSH Term Description Entries
D008175 Lung Neoplasms Tumors or cancer of the LUNG. Cancer of Lung,Lung Cancer,Pulmonary Cancer,Pulmonary Neoplasms,Cancer of the Lung,Neoplasms, Lung,Neoplasms, Pulmonary,Cancer, Lung,Cancer, Pulmonary,Cancers, Lung,Cancers, Pulmonary,Lung Cancers,Lung Neoplasm,Neoplasm, Lung,Neoplasm, Pulmonary,Pulmonary Cancers,Pulmonary Neoplasm
D002289 Carcinoma, Non-Small-Cell Lung A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy. Carcinoma, Non-Small Cell Lung,Non-Small Cell Lung Cancer,Non-Small Cell Lung Carcinoma,Non-Small-Cell Lung Carcinoma,Nonsmall Cell Lung Cancer,Carcinoma, Non Small Cell Lung,Carcinomas, Non-Small-Cell Lung,Lung Carcinoma, Non-Small-Cell,Lung Carcinomas, Non-Small-Cell,Non Small Cell Lung Carcinoma,Non-Small-Cell Lung Carcinomas
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000082082 Immune Checkpoint Inhibitors Drugs that block negative regulator IMMUNE CHECKPOINT proteins (e.g., PD-1 RECEPTOR and CTLA-4 ANTIGEN) thereby increasing suppressed immune activation in immunotherapies. CTLA-4 Inhibitor,CTLA-4 Inhibitors,Cytotoxic T-Lymphocyte-Associated Protein 4 Inhibitor,Cytotoxic T-Lymphocyte-Associated Protein 4 Inhibitors,Immune Checkpoint Blockade,Immune Checkpoint Blockers,Immune Checkpoint Inhibition,Immune Checkpoint Inhibitor,PD-1 Inhibitor,PD-1 Inhibitors,PD-1-PD-L1 Blockade,PD-L1 Inhibitor,PD-L1 Inhibitors,Programmed Cell Death Protein 1 Inhibitor,Programmed Cell Death Protein 1 Inhibitors,Programmed Death-Ligand 1 Inhibitors,Blockade, PD-1-PD-L1,CTLA 4 Inhibitor,CTLA 4 Inhibitors,Checkpoint Blockade, Immune,Checkpoint Blockers, Immune,Checkpoint Inhibition, Immune,Checkpoint Inhibitor, Immune,Checkpoint Inhibitors, Immune,Cytotoxic T Lymphocyte Associated Protein 4 Inhibitor,Cytotoxic T Lymphocyte Associated Protein 4 Inhibitors,Inhibitor, PD-1,PD 1 Inhibitor,PD 1 Inhibitors,PD 1 PD L1 Blockade,PD L1 Inhibitor,PD L1 Inhibitors,Programmed Death Ligand 1 Inhibitors
D012189 Retrospective Studies Studies used to test etiologic hypotheses in which inferences about an exposure to putative causal factors are derived from data relating to characteristics of persons under study or to events or experiences in their past. The essential feature is that some of the persons under study have the disease or outcome of interest and their characteristics are compared with those of unaffected persons. Retrospective Study,Studies, Retrospective,Study, Retrospective
D016246 Lymphocytes, Tumor-Infiltrating Lymphocytes that show specificity for autologous tumor cells. Ex vivo isolation and culturing of TIL with interleukin-2, followed by reinfusion into the patient, is one form of adoptive immunotherapy of cancer. Tumor Infiltrating Lymphocyte,Tumor-Derived Activated Cell,Tumor-Derived Activated Cells,Tumor-Infiltrating Lymphocyte,Tumor-Infiltrating Lymphocytes,Activated Cell, Tumor-Derived,Activated Cells, Tumor-Derived,Infiltrating Lymphocyte, Tumor,Infiltrating Lymphocytes, Tumor,Lymphocyte, Tumor Infiltrating,Lymphocyte, Tumor-Infiltrating,Lymphocytes, Tumor Infiltrating,Tumor Derived Activated Cell,Tumor Derived Activated Cells,Tumor Infiltrating Lymphocytes
D051017 Apoptosis Regulatory Proteins A large group of proteins that control APOPTOSIS. This family of proteins includes many ONCOGENE PROTEINS as well as a wide variety of classes of INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS such as CASPASES. Anti-Apoptotic Protein,Anti-Apoptotic Proteins,Apoptosis Inducing Protein,Apoptosis Inhibiting Protein,Apoptosis Regulatory Protein,Pro-Apoptotic Protein,Pro-Apoptotic Proteins,Programmed Cell Death Protein,Apoptosis Inducing Proteins,Apoptosis Inhibiting Proteins,Death Factors (Apoptosis),Programmed Cell Death Proteins,Survival Factors (Apoptosis),Anti Apoptotic Protein,Anti Apoptotic Proteins,Inducing Protein, Apoptosis,Inducing Proteins, Apoptosis,Inhibiting Protein, Apoptosis,Inhibiting Proteins, Apoptosis,Pro Apoptotic Protein,Pro Apoptotic Proteins,Protein, Anti-Apoptotic,Protein, Apoptosis Inducing,Protein, Apoptosis Inhibiting,Protein, Apoptosis Regulatory,Protein, Pro-Apoptotic,Proteins, Anti-Apoptotic,Proteins, Apoptosis Inducing,Proteins, Apoptosis Inhibiting,Proteins, Pro-Apoptotic,Regulatory Protein, Apoptosis,Regulatory Proteins, Apoptosis
D059016 Tumor Microenvironment The milieu surrounding neoplasms consisting of cells, vessels, soluble factors, and molecules, that can influence and be influenced by, the neoplasm's growth. Cancer Microenvironment,Cancer Microenvironments,Microenvironment, Cancer,Microenvironment, Tumor,Microenvironments, Cancer,Microenvironments, Tumor,Tumor Microenvironments
D060890 B7-H1 Antigen An inhibitory B7 antigen that contains V-type and C2 type immunoglobulin domains. It has specificity for the T-CELL receptor PROGRAMMED CELL DEATH 1 PROTEIN and provides negative signals that control and inhibit T-cell responses. It is found at higher than normal levels on tumor cells, suggesting its potential role in TUMOR IMMUNE EVASION. Antigens, CD274,PD-L1 Protein,Programmed Cell Death 1 Ligand 1 Protein,Programmed Death Ligand 1,B7-H1 Immune Costimulatory Protein,B7H1 Immune Costimulatory Protein,CD274 Antigen,PD-L1 Costimulatory Protein,Programmed Cell Death 1 Ligand 1,Antigen, B7-H1,Antigen, CD274,B7 H1 Antigen,B7 H1 Immune Costimulatory Protein,CD274 Antigens,Costimulatory Protein, PD-L1,PD L1 Costimulatory Protein,PD L1 Protein
D018414 CD8-Positive T-Lymphocytes A critical subpopulation of regulatory T-lymphocytes involved in MHC Class I-restricted interactions. They include both cytotoxic T-lymphocytes (T-LYMPHOCYTES, CYTOTOXIC) and CD8+ suppressor T-lymphocytes. Suppressor T-Lymphocytes, CD8-Positive,T8 Cells,T8 Lymphocytes,CD8-Positive Lymphocytes,Suppressor T-Cells, CD8-Positive,CD8 Positive Lymphocytes,CD8 Positive T Lymphocytes,CD8-Positive Lymphocyte,CD8-Positive Suppressor T-Cell,CD8-Positive Suppressor T-Cells,CD8-Positive Suppressor T-Lymphocyte,CD8-Positive Suppressor T-Lymphocytes,CD8-Positive T-Lymphocyte,Cell, T8,Cells, T8,Lymphocyte, CD8-Positive,Lymphocyte, T8,Lymphocytes, CD8-Positive,Lymphocytes, T8,Suppressor T Cells, CD8 Positive,Suppressor T Lymphocytes, CD8 Positive,Suppressor T-Cell, CD8-Positive,Suppressor T-Lymphocyte, CD8-Positive,T-Cell, CD8-Positive Suppressor,T-Cells, CD8-Positive Suppressor,T-Lymphocyte, CD8-Positive,T-Lymphocyte, CD8-Positive Suppressor,T-Lymphocytes, CD8-Positive,T-Lymphocytes, CD8-Positive Suppressor,T8 Cell,T8 Lymphocyte

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