Abstract A077: Microenvironmental factors shape resistance patterns to immune checkpoint blockade

Immune checkpoint blockade (ICB) therapy has dramatically improved the prognosis of several types of cancer. However, only a small proportion of patients respond. Although multiple biomarkers/mechanisms of resistance to ICB have been identified, it remains elusive to what extent the cellular/molecular mechanisms contribute to the heterogeneity of ICB response. To this end, we applied clonal barcoding for lineage tracing of cancer cells following control IgG or ICB treatment in a transplantation mouse model. We identified significant clonal heterogeneity within cancer cells in response to ICB, suggestive of a minority of pre-existing ICB-resistant clones prior to treatment. Furthermore, counter-intuitively, ICB-responding tumors harbored a higher proportion of ICB-resistant clones than nonresponding tumors post-treatment, indicating that the tumor microenvironment might dictate the initial response to ICB. Integrated gene expression and immune repertoire analyses of the tumor microenvironment identified more T-cell and B cell infiltration in the ICB responders, and found that BCR class switch is associated with ICB response. Our study established a system to assess the contributions of cancer cell-intrinsic and microenvironmental factors in response to ICB treatment, and identified B cell infiltration and repertoire constitution as a novel biomarker for ICB response. Citation Format: Shengquing Stan Gu, Xihao Sherlock Hu, Xiaoqing Shawn Wang, Ziyi Li, Nicole Traugh, Xia Bu, Xiaofang Xing, Gordon Freeman, Myles Brown, Xiaole Shirley Liu. Microenvironmental factors shape resistance patterns to immune checkpoint blockade [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 A077.