Abstract 2934: Neoadjuvant chemotherapy influence changes of the immune response in non-small cell lung carcinomas immune response in non-small cell lung carcinomas
Authors: Cuentas Edwin Roger , Behrens Carmen , Rodriguez-Canales Jaime , Jiang Mei , Pataer Apar , Correa Arelene , Swisher Stephen , Sepesi Boris , Weissferdt Annikka , Kalhor Neda , Zhang Jiexin , Lee Jack , Heymach John , Moran Cesar , Zhang Jianjun , Gibbons Don , Wistuba Ignacio 
Published: July 2017

Abstract
Background: The clinical efficacy observed with PD-1/PD-L1 inhibitors in non-small cell lung carcinoma (NSCLC) has prompted to characterize the immune response in lung tumors treated with chemotherapy. The aim of this study was to determine the changes of the immune microenvironment in surgically resected NSCLCs from patients who received and did not receive neo-adjuvant chemotherapy.
Methods: We studied formalin-fixed and paraffin embedded (FFPE) tumor tissues from 112 stage II/III resected NSCLC, including 61 chemotherapy-naïve (adenocarcinoma, ADC=33; squamous cell carcinoma, SCC=28) and 51 chemotherapy-treated (ADC=31; SCC=20) tumors. mIF was performed using the Opal 7-color fIHC Kit™, scanning in the Vectra™ multispectral microscope and analyzed using the inForm™ software (Perkin Elmer, Waltham, MA). The markers studied were grouped in two 6-antibody panels: Panel 1, AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD4, CD8 and CD68; and Panel 2, AE1/AE3, PD1, Granzyme B, FOXP3, CD45RO and CD57.
Results: Positive PD-L1 expression (&gt;5%) in malignant cells (MCs) was detected in 48% (n=53/112) of NSCLCs. Overall, chemotherapy-treated tumors showed significantly higher percentages of MCs expressing PD-L1 (median, 19.52%) than chemotherapy-naïve cases (median, 1.54%; P=0.008). Higher densities of lymphocytes expressing CD3+ (P=0.021), CD4+ (P=0.05), CD57 (P&lt;0.001), CD45RO+ (P=0.019), and PD-1 (P=0.016) were detected in chemotherapy-treated NSCLCs compared with chemo-naïve tumors. In contrast, lower densities of FOXP3+ regulatory T cells and CD68+ macrophages but not statistical significant were detected in chemotherapy-naïve tumors when compared with chemotherapy-treated cases. Following chemotherapy ADCs exhibited significantly higher levels of CD57+ (P=0.008) and high density of PD-1 expressing by CD45RO+ cells (P=0.016) than chemotherapy-naïve tumors. Chemotherapy-treated SCCs demonstrated higher density of TAMs CD68+, CD57+,CD45RO+ and PD-1 cells than chemotherapy-naïve tumors (P&lt;0.05). In chemotherapy-treated cancers, lower levels of CD4+ helper T cells was associated with worse overall survival (OS; P=0.04) in univariate analysis. In chemotherapy-treated ADC patients, lower levels of CD68-positive (P=0.010) and higher levels of FOXP3-positive cells correlated with worse OS (P=0.044).
Conclusions: Neo-adjuvant chemotherapy-treated NSCLCs exhibited higher levels of PD-L1 expression and T cell subsets regulation compared to chemotherapy-naïve tumors, suggesting that chemotherapy activates specific immune response mechanisms in lung cancer. These results provide an inclination towards the design of clinical trials combining neo-adjuvant chemotherapy and immunotherapy prior to surgical resection of locally advanced NSCLC. (Supported by CPRIT MIRA and UT Lung SPORE grants, and MD Anderson Moon Shot Program).
Citation Format: Edwin Roger Cuentas, Carmen Behrens, Jaime Rodriguez-Canales, Mei Jiang, Apar Pataer, Arelene Correa, Stephen Swisher, Boris Sepesi, Annikka Weissferdt, Neda Kalhor, Jiexin Zhang, Jack Lee, John Heymach, Cesar Moran, Jianjun Zhang, Don Gibbons, Ignacio Wistuba. Neoadjuvant chemotherapy influence changes of the immune response in non-small cell lung carcinomas immune response in non-small cell lung carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2934. doi:10.1158/1538-7445.AM2017-2934