Abstract A059: Tackling the tumor microenvironment with CD38 blockade to enhance cancer immunotherapy
Authors: Chen Limo , Diao Lixia , Yi Xiaohui , Rodriguez Bertha Leticia , Li Yanli , Villalobos Pamela , Cascone Tina , Liu Xi , Tan Lin , Lorenzi Philip , Fradette Jared , Peng David , Skoulidis Ferdinandos , Fan Youhong , Rodriguez-Canales Jaime , Papadimitrakopoulou Vassiliki , Dmitrovsky Ethan , Byers Lauren A , Wang Jing , Wistuba Ignasio , Heymach Jim , Gibbons Don 
Published: February 2019

Abstract
The single agent or the combination of anti-PD-1, anti-PD-L1, and anti-CTLA-4 is an effective strategy that is being clinically explored to treat a variety of cancer types. Some patients display primary resistance to the treatment, while others relapse after treatment. Resistance is a major issue that needs to be addressed. Using multiple immunocompetent syngeneic and K-rasLA1/+p53R172HΔg/+ spontaneous animal models of lung cancer, we have explored the mechanisms of resistance to treatments by evaluating the molecular and cellular immune profiles of the tumor microenvironment. We observed that tumor-bearing mice treated with PD-1/PD-L1 blocking antibodies developed resistance through the up-regulation of CD38. We also observed this in the combination therapy of anti-PD-1 and anti-CTLA-4, suggesting that CD38 is a major mechanism of resistance to immune checkpoint inhibitors. In vitro and in vivo studies demonstrated that CD38 impacted CD8+ T-cell function via adenosine receptor signaling and dendritic cell-mediated B7 signaling. Antibody-mediated cell depletion assays were conducted to validate the mechanisms. To determine the applicability to patients, we analyzed 793 lung cancer patients’ specimens with immunohistochemistry staining and assessed biomarker relationships in multiple large independent patient databases (~1,900 tumors). Pathologic analysis revealed positive immunohistochemical staining for CD38 on tumor cells in 15-23% of cases, and bioinformatic analyses revealed a strong correlation between CD38 expression and the immune signature. Lastly, targeting CD38 abolished the treatment resistance by modulating the adenosine levels and thereby enhancing the effector immune cell infiltrates into the tumor microenvironment. Based on our study, CD38 blockade improves the efficacy of single-agent anti-PD-1/PD-L1, or with anti-CTLA-4 combination in lung cancer. CD38 could potentially serve as a novel biomarker of resistance for immune checkpoint inhibition. The data from this study provide a unique target, biomarker, and therapeutic strategy that can be translated into the clinical practice.
Citation Format: Limo Chen, Lixia Diao, Xiaohui Yi, Bertha Leticia Rodriguez, Yanli Li, Pamela Villalobos, Tina Cascone, Xi Liu, Lin Tan, Philip Lorenzi, Jared Fradette, David Peng, Ferdinandos Skoulidis, Youhong Fan, Jaime Rodriguez-Canales, Vassiliki Papadimitrakopoulou, Ethan Dmitrovsky, Lauren A Byers, Jing Wang, Ignasio Wistuba, Jim Heymach, Don Gibbons. Tackling the tumor microenvironment with CD38 blockade to enhance cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A059.