Abstract 4256: High programmed cell death ligand 1 expression and low immune infiltrate score correlate with worse outcome in patients with lung adenocarcinoma
Authors: Parra Edwin R. , Behrens Carmen , Rodriguez-Canales Jaime , Lin Heather , Mino Barbara , Blando Jorge , Lou Yanyan , Gibbons Don L. , Heymach John V. , Swisher Stephen G. , Weissferdt Annikka , Kahlor Neda , Izzo Julie , Lee J. Jack , Kadara Humam , Moran Cesar , Wistuba Ignacio 
Published: August 2015

Abstract
Background: Programmed cell death ligand 1 (PD-L1) is a major immune checkpoint protein that mediates anti-tumor immune suppression and response. Indeed, the importance of PD-L1 based immune suppression is highlighted by the advent of anti-PD-L1 immunotherapies that have moved to the forefront of lung cancer treatment. A better understanding of the “profile” of PD-L1 expression and its interplay with immune cells will provide important insights into lung cancer pathogenesis, and thus, improve immunotherapeutic strategies targeting this important immune checkpoint protein. The goal of this study was to investigate the correlation between immunohistochemical (IHC) expression of PD-L1 and the density and nature of tumor infiltrating immune cells in surgically resected lung adenocarcinomas, and correlate those profiles with clinical and pathological variables including patient outcome.
Methods: We examined 146 stages I-III lung adenocarcinomas using whole tissue sections obtained from formalin-fixed and paraffin-embedded tissues. PDL-1 expression on tumor cells and density of inflammatory cells expressing PD-1, CD3, CD4, CD8, CD45RO, CD57, CD68, Granzyme B and FOXP3 were evaluated by automated IHC and quantified using image analysis in intra-tumoral (IT) and peri-tumoral (PT) compartments. PD-L1 expression was scored as positive if at least 5% of tumor cells showed membranous staining, and an immune-score (IMS) using CD8/CD4/CD68 was devised. KRAS and EGFR mutation status were available.
Results: Thirty-four (23%) of 146 tumors had positive levels of PD-L1 IHC expression in malignant cells. Higher levels of PD-L1 expression were detected in tumors with solid histology pattern compared with other histologies (P = 0.034), and in lifetime smokers compared with non-smokers (P&lt;0.0001). PDL-1 expression correlated positively with inflammatory cell density in both IT and PT compartments. KRAS mutant tumors with solid pattern showed significantly higher levels of PD-L1 and PD-1 expressions, and IMS, compared with non-solid tumors (P = 0.001). Using PD-L1 and CD8/CD4/CD68 IMS expression levels, we identified 4 groups of tumors: PD-L1high/IMShigh 18%; PD-L1high/IMSlow 5%; PD-L1low/IMShigh 35%; and, PD-L1low/IMSlow 42%. Finally, multivariate Cox proportional hazard regression analysis demonstrated that tumors with high PD-L1 expression and low IMS exhibited significantly poor recurrence-free (HR = 8.975; P&lt;0.0001) and overall survival (HR = 4.220; P = 0.0015).
Conclusions: In lung adenocarcinoma, PD-L1 expression correlates with less differentiated tumors and higher level of tumoral immune infiltrate. We developed a lung adenocarcinoma IMS which when combined with PD-L1 expression significantly correlates with patient outcome when analyzed in surgically resected tumors specimens. (Supported by grants UT-Lung SPORE P50CA70907 and CPRIT RP120713).
Citation Format: Edwin R. Parra, Carmen Behrens, Jaime Rodriguez-Canales, Heather Lin, Barbara Mino, Jorge Blando, Yanyan Lou, Don L. Gibbons, John V. Heymach, Stephen G. Swisher, Annikka Weissferdt, Neda Kahlor, Julie Izzo, J. Jack Lee, Humam Kadara, Cesar Moran, Ignacio Wistuba. High programmed cell death ligand 1 expression and low immune infiltrate score correlate with worse outcome in patients with lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4256. doi:10.1158/1538-7445.AM2015-4256