Daniel J Gross1, Navin K Chintala1, Raj G Vaghjiani1, Rachel Grosser1, Kay See Tan2, Xiaoyu Li3, Jennie Choe1, Yan Li4, Rania G Aly5, Katsura Emoto6, Hua Zheng7, Joseph Dux1, Waseem Cheema1, Matthew J Bott1, William D Travis8, James M Isbell1, Bob T Li9, David R Jones1, Prasad S Adusumilli10. 1. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. 2. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 3. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, People's Republic of China. 4. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pathology, Union Hospital, Tongi Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 5. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pathology, Alexandria University, Alexandria, Egypt. 6. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pathology, Keio University School of Medicine, Tokyo, Japan. 7. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing, People's Republic of China. 8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. 9. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 10. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: adusumip@mskcc.org.
Abstract
INTRODUCTION: Patients with stage II to III lung adenocarcinomas are treated with adjuvant chemotherapy (ACT) to target the premetastatic niche that persists after curative-intent resection. We hypothesized that the premetastatic niche is a scion of resected lung tumor microenvironment and that analysis of tumor microenvironment can stratify survival benefit from ACT. METHODS: Using tumor and tumoral stroma from 475 treatment-naive patients with stage II to III lung adenocarcinomas, we constructed a tissue microarray and performed multiplex immunofluorescent staining for immune markers (programmed death-ligand 1 [PD-L1], tumor-associated macrophages [TAMs], and myeloid-derived suppressor cells) and derived myeloid-lymphoid ratio. The association between immune markers and survival was evaluated using Cox models adjusted for pathologic stage. RESULTS: Patients with high PD-L1 expression on TAMs or tumor cells in resected tumors had improved survival with ACT (TAMs: hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.12-2.85; tumor cells: HR = 3.02, 95% CI: 1.69-5.40). Among patients with high PD-L1 expression on TAMs alone or TAMs and tumor cells, ACT survival benefit is pronounced with high myeloid-lymphoid ratio (TAMs: HR = 3.87, 95% CI: 1.79-8.37; TAMs and tumor cells: HR = 2.19, 95% CI: 1.02-4.71) or with high stromal myeloid-derived suppressor cell ratio (TAMs: HR = 2.53, 95% CI: 1.29-4.96; TAMs and tumor cells: HR = 3.21, 95% CI: 1.23-8.35). Patients with low or no PD-L1 expression on TAMs or tumor cells had no survival benefit from ACT. CONCLUSIONS: Our observation that PD-L1 expression on TAMs or tumor cells is associated with improved survival with ACT provides rationale for prospective investigation and developing chemoimmunotherapy strategies for patients with lung adenocarcinoma.
INTRODUCTION: Patients with stage II to III lung adenocarcinomas are treated with adjuvant chemotherapy (ACT) to target the premetastatic niche that persists after curative-intent resection. We hypothesized that the premetastatic niche is a scion of resected lung tumor microenvironment and that analysis of tumor microenvironment can stratify survival benefit from ACT. METHODS: Using tumor and tumoral stroma from 475 treatment-naive patients with stage II to III lung adenocarcinomas, we constructed a tissue microarray and performed multiplex immunofluorescent staining for immune markers (programmed death-ligand 1 [PD-L1], tumor-associated macrophages [TAMs], and myeloid-derived suppressor cells) and derived myeloid-lymphoid ratio. The association between immune markers and survival was evaluated using Cox models adjusted for pathologic stage. RESULTS: Patients with high PD-L1 expression on TAMs or tumor cells in resected tumors had improved survival with ACT (TAMs: hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.12-2.85; tumor cells: HR = 3.02, 95% CI: 1.69-5.40). Among patients with high PD-L1 expression on TAMs alone or TAMs and tumor cells, ACT survival benefit is pronounced with high myeloid-lymphoid ratio (TAMs: HR = 3.87, 95% CI: 1.79-8.37; TAMs and tumor cells: HR = 2.19, 95% CI: 1.02-4.71) or with high stromal myeloid-derived suppressor cell ratio (TAMs: HR = 2.53, 95% CI: 1.29-4.96; TAMs and tumor cells: HR = 3.21, 95% CI: 1.23-8.35). Patients with low or no PD-L1 expression on TAMs or tumor cells had no survival benefit from ACT. CONCLUSIONS: Our observation that PD-L1 expression on TAMs or tumor cells is associated with improved survival with ACT provides rationale for prospective investigation and developing chemoimmunotherapy strategies for patients with lung adenocarcinoma.
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