Prognostic Relevance of the Relative Presence of CD4, CD8 and CD20 Expressing Tumor Infiltrating Lymphocytes in Operable Non-small Cell Lung Cancer Patients.

Non-small cell lung cancer (NSCLC) is one of the most lethal tumors. Given the failure of conventional therapeutic strategies, immunotherapy has emerged as a promising treatment modality that may improve the survival of patients with operable and advanced disease. We examined the relative presence of CD20+ B-cells, CD8+ cytotoxic, and CD4+ helper/regulatory T-cells in the tumor-infiltrating lymphocyte (TIL)-population in a series of surgically-treated NSCLCs, and assessed their role as prognostic indicators after surgery. A high percent of CD4+ and CD8+ TILs in the tumor stroma was linked with poor (p=0.003) and good prognosis (p=0.01), respectively. High CD4/CD8 ratio defined a significantly worst prognosis [median survival 22 months vs. undefined, p=0.0002, hazard ratio (HR) 0.3 vs. 3.0]. Statistically significant results were also noted when the analysis was focused on the invading tumor front. In a multivariate model, the CD4/CD8-ratio assessed in the tumor stroma and the stage of disease were independent prognostic variables (p=0.0001, HR=4.1 and p=0.001, HR=1.5, respectively). The balance between CD4+ and CD8+ lymphocytes infiltrating the tumor stroma is a crucial factor defining anti-tumor immune surveillance, has strong prognostic value, and may be tested as a predictive biomarker for immunotherapy in operable NSCLC.

Giatromanolaki A ，Anestopoulos I ，Panayiotidis MI ，Mitrakas A ，Pappa A ，Koukourakis MI ... -  《-》

Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer.

T-cell infiltration in tumors has been used as a prognostic tool in non-small-cell lung cancer (NSCLC). However, the influence of smoking habit and histological type on tumor-infiltrating lymphocytes (TILs) in NSCLC remains unclear. We evaluated the prognostic significance of TILs (CD4+, CD8+, CD20+, and FOXP3+) according to histological type and smoking habit using automatic immunohistochemical staining and cell counting in 218 patients with NSCLC. In multivariate survival analyses of clinical, pathological, and immunological factors, a high ratio of FOXP3+ to CD4+ T cells (FOXP3/CD4) [hazard ratio (HR): 4.46, P < 0.01 for overall survival (OS); HR: 1.96, P < 0.05 for recurrence-free survival (RFS)] and a low accumulation of CD20+ B cells (HR: 2.45, P = 0.09 for OS; HR: 2.86, P < 0.01 for RFS) were identified as worse prognostic factors in patients with adenocarcinoma (AD). In non-AD, a low number of CD8+ T cells were correlated with an unfavorable outcome (HR: 7.69, P < 0.01 for OS; HR: 3.57, P < 0.02 for RFS). Regarding smoking habit in AD, a high FOXP3/CD4 ratio was poorly prognostic with a smoking history (HR: 5.21, P < 0.01 for OS; HR: 2.38, P < 0.03 for RFS), whereas a low accumulation of CD20+ B cells (HR: 4.54, P = 0.03 for OS; HR: 2.94, P < 0.01 for RFS) was confirmed as an unfavorable factor in non-smokers with AD. A low number of CD8+ T cells in non-AD, a high FOXP3/CD4 ratio in smokers with AD, and a low number of CD20+ B cells in non-smokers with AD were identified as independent unfavorable prognostic factors in resected NSCLC. Evaluating the influence of histological type and smoking habit on the immunological environment may lead to the establishment of immunological diagnosis and appropriate individualized immunotherapy for NSCLC.

Kinoshita T ，Muramatsu R ，Fujita T ，Nagumo H ，Sakurai T ，Noji S ，Takahata E ，Yaguchi T ，Tsukamoto N ，Kudo-Saito C ，Hayashi Y ，Kamiyama I ，Ohtsuka T ，Asamura H ，Kawakami Y ... -  《-》

Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer.

Al-Shibli KI ，Donnem T ，Al-Saad S ，Persson M ，Bremnes RM ，Busund LT ... -  《CLINICAL CANCER RESEARCH》

Antigen-Presenting Intratumoral B Cells Affect CD4(+) TIL Phenotypes in Non-Small Cell Lung Cancer Patients.

Effective immunotherapy options for patients with non-small cell lung cancer (NSCLC) are becoming increasingly available. The immunotherapy focus has been on tumor-infiltrating T cells (TILs); however, tumor-infiltrating B cells (TIL-Bs) have also been reported to correlate with NSCLC patient survival. The function of TIL-Bs in human cancer has been understudied, with little focus on their role as antigen-presenting cells and their influence on CD4+ TILs. Compared with other immune subsets detected in freshly isolated primary tumors from NSCLC patients, we observed increased numbers of intratumoral B cells relative to B cells from tumor-adjacent tissues. Furthermore, we demonstrated that TIL-Bs can efficiently present antigen to CD4+ TILs and alter the CD4+ TIL phenotype using an in vitro antigen-presentation assay. Specifically, we identified three CD4+ TIL responses to TIL-Bs, which we categorized as activated, antigen-associated, and nonresponsive. Within the activated and antigen-associated CD4+ TIL population, activated TIL-Bs (CD19+CD20+CD69+CD27+CD21+) were associated with an effector T-cell response (IFNγ+ CD4+ TILs). Alternatively, exhausted TIL-Bs (CD19+CD20+CD69+CD27-CD21-) were associated with a regulatory T-cell phenotype (FoxP3+ CD4+ TILs). Our results demonstrate a new role for TIL-Bs in NSCLC tumors in their interplay with CD4+ TILs in the tumor microenvironment, establishing them as a potential therapeutic target in NSCLC immunotherapy. Cancer Immunol Res; 5(10); 898-907. ©2017 AACR.

Bruno TC ，Ebner PJ ，Moore BL ，Squalls OG ，Waugh KA ，Eruslanov EB ，Singhal S ，Mitchell JD ，Franklin WA ，Merrick DT ，McCarter MD ，Palmer BE ，Kern JA ，Slansky JE ... -  《-》

The role of tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in patients with metastatic non-small cell lung cancer or metastatic melanoma.

Uryvaev A ，Passhak M ，Hershkovits D ，Sabo E ，Bar-Sela G ... -  《-》