Tumor PD-L1 and VEGF Expression, and CD8 T Cell Infiltration Predict Clinical Response to Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

We evaluated the efficacy of "the tumor immune microenvironment (TIME) classification" for predicting clinical response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). In addition, we aimed to evaluate the "modified TIME classification", which adds the vascular endothelial growth factor (VEGF) status to TIME. Programmed cell death receptor ligand-1 (PD-L1), CD8 T cell tumor-infiltrating lymphocytes (CD8+TILs) count and VEGF expression analyses were performed using immuno - histochemistry in 44 patients who had undergone ICI monotherapy. Regarding TIME classification, type-I (PD-L1 high and CD8+TILs high) had a significantly higher response than the other types. Using the modified TIME classification, type-IA (PD-L1 high, CD8+TILs high, and VEGF low) had a significantly higher response than the other types. The modified TIME classification, which adds tumor VEGF expression to "the TIME classification", could be useful in predicting clinical response to ICI monotherapy.

Nojima Y ，Shimizu K ，Saisho S ，Maeda AI ，Kurosaki T ，Kurose K ，Oga T ，Oka M ，Nakata M ... -  《-》

Smoking History Predicts High Presence of TILs and Efficacy of PD-1 Blockade in PD-L1 Expression-negative Non-small Cell Lung Cancer Patients.

Programmed death-ligand 1 (PD-L1) expression on tumor cells is a predictive biomarker of programmed cell death 1 (PD-1) blockade therapy. This study sought to clarify predictors of the efficacy of nivolumab in non-small cell lung cancer (NSCLC) patients with PD-L1 expression-negative tumors. We retrospectively reviewed the records of advanced NSCLC patients between January 2016 and April 2019, and investigated the predictive marker of nivolumab including the status of CD8+ tumor infiltrating lymphocytes (TILs). A total of 70 NSCLC patients were included. Overall response rate (ORR) and progression-free survival (PFS) were better in patients with a heavy smoking history (smoking index: SI≥600) than in those without (SI<600) [ORR: 20.6% vs. 2.8%, (p=0.02), and PFS: 2.4 months vs. 1.8 months, (p=0.04)]. A high density of CD8+ TILs was significantly associated with a heavy smoking history (p=0.04). Conlusion: Heavy smoking history (SI≥600), which was correlated with a large number of CD8+ TILs, could be a predictor of the efficacy of nivolumab in NSCLC patients with PD-L1 expression-negative tumors.

Shimoda Y ，Yoshida T ，Shirasawa M ，Mizuno T ，Jo H ，Matsumoto Y ，Shinno Y ，Okuma Y ，Goto Y ，Horinouchi H ，Yamamoto N ，Yatabe Y ，Ohe Y ，Motoi N ... -  《-》

Elucidation of the relationships of MET protein expression and gene copy number status with PD-L1 expression and the immune microenvironment in non-small cell lung cancer.

Alterations in the MET gene, such as mutations and high-level amplification, are important drivers of non-small cell lung cancer (NSCLC). The efficacy of immune checkpoint inhibitors (ICIs) in lung cancer with MET abnormalities is unclear. We evaluate the potential relationship between MET alterations and the tumor immune microenvironment and PD-1/PD-L1 axis. MET and phospho-MET protein expression were assessed in 622 resected NSCLC specimens. MET amplification was assessed by fluorescence in-situ hybridization in 272 tumors. PD-L1 expression was evaluated by immunohistochemistry. CD8+, Foxp3+, CD45RO, and PD-1+ tumor-infiltrating lymphocytes (TILs) in the tumor nest and surrounding stroma were profiled. Associations with MET alterations were explored. The cohort comprised 425 male patients (68.3 %), 184 never-smokers (29.6 %), and 408 adenocarcinoma (ADC) patients (65.6 %). Median age was 68 years. MET alteration was observed mainly in ADCs (18.9 % MET-positive, 3.9 % phospho-MET-positive, and 15.1 % with MET amplification). PD-L1 expression was significantly increased in MET-altered ADCs (P < 0.001 for MET; P = 0.002 for phospho-MET; P = 0.019 for MET amplification). Most TIL subset numbers in the tumor nest were significantly increased in MET-altered tumors. Only MET amplification was independently associated with tumoral CD8 + TILs. Three of the six patients responded to ICI treatment; two of them showed MET overexpression and an increase in MET copy number. MET-altered tumors showed significantly stronger PD-L1 expression and more abundant tumoral TILs than non-MET-altered tumors. Among the MET alterations assessed, MET amplification was particularly implicated in the inflamed microenvironment, suggesting that MET-amplified tumors might respond to ICIs.

Yoshimura K ，Inoue Y ，Tsuchiya K ，Karayama M ，Yamada H ，Iwashita Y ，Kawase A ，Tanahashi M ，Ogawa H ，Inui N ，Funai K ，Shinmura K ，Niwa H ，Suda T ，Sugimura H ... -  《-》

Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer.

Reinvigoration of T-cell exhaustion with antibodies has shown promising efficacy in patients with non-small-cell lung cancer (NSCLC). However, the characteristics of T-cell exhaustion with regard to tumor-infiltrating lymphocytes (TILs) are poorly elucidated in NSCLC. Here, we investigated the exhaustion status of TILs in NSCLC patients at the intraindividual and interindividual levels. We obtained paired peripheral blood, normal adjacent tissues, peritumoral tissues, and tumor tissues from 96 NSCLC patients. Features of T-cell exhaustion were analyzed by flow cytometry. T cells were categorized according to their programmed cell death-1 (PD-1) expression (PD-1high, PD-1int, and PD-1neg cells). Patients were classified based on the presence or absence of discrete PD-1high CD8+ TILs. Production of effector cytokines by CD8+ TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors. Progressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1high CD8+ TILs compared with PD-1int and PD-1neg CD8+ TILs. Patients with distinct PD-1high CD8+ TILs (PD-1high expressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1high expressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8+ TILs following T-cell stimulation. PD-1high CD8+ T lymphocyte populations in the peripheral blood and tumors were significantly correlated. T-cell exhaustion was differentially regulated among individual patients and was prominent in a subgroup of NSCLC patients who may benefit from PD-1 blockade or combined blockade of other immune checkpoint receptors.

Kim CG ，Kim G ，Kim KH ，Park S ，Shin S ，Yeo D ，Shim HS ，Yoon HI ，Park SY ，Ha SJ ，Kim HR ... -  《Journal for ImmunoTherapy of Cancer》

Serum-derived exosomal PD-L1 expression to predict anti-PD-1 response and in patients with non-small cell lung cancer.

Shimada Y ，Matsubayashi J ，Kudo Y ，Maehara S ，Takeuchi S ，Hagiwara M ，Kakihana M ，Ohira T ，Nagao T ，Ikeda N ... -  《Scientific Reports》