Abstract A018: Deconvolving the cell-specific actions of SHP2 inhibitors in the lung cancer tumor microenvironment reveals requirement for SHP2 in B-regulatory cell development

Abstract Lung cancer is the leading cause of cancer death worldwide and lung adenocarcinoma (LUAD) accounts for most of these cases. Despite impressive advances in LUAD biology and new therapies, 5-year survival from stage-IV LUAD remains dismal (<10%), and improving LUAD outcomes represents a major, urgent, unmet medical need. Current LUAD therapeutics include “conventional” (chemoradiation), “targeted”, and “immune” (e.g., checkpoint inhibitor) agents. These modalities improve patient outcomes, but they are far from panaceas. Chemoradiation and targeted therapies extend survival, but disease inevitably recurs owing to multiple resistance mechanisms. Immune therapies can cure other malignancies (e.g., melanoma), but only some LUAD patients respond, and even they are not cured. Combinations of conventional, targeted, and immune therapies will probably be needed to cure most, if not all, advanced LUAD patients, and cure of LUAD (or any malignancy) likely requires generation of a durable anti-tumor immune response. Hence, to optimally deploy any conventional or targeted agent, we must understand its effects on cancer cells and cells in the tumor microenvironment (TME). To this end, we developed unique genetically engineered mouse models (GEMMs) to interrogate the cancer cell-autonomous and non-autonomous actions of the protein-tyrosine phosphatase SHP2 (encoded by Ptpn11) and SHP2 inhibitors (SHP2is) in Kras-mutant (Kras G12D ;Trp53 -/-, “KP”) LUAD. These include mice with cell-specific expression of an SHP2i resistant Ptpn11 mutant (Ptpn11 P491Q ) or cell-specific Ptpn11 f/f deletion. Perhaps surprisingly, neither deletion of SHP2 in T cells nor inability of SHP2i to act in T cells affected KP LUAD growth. Instead, we found that metastatic KP LUAD is associated with tumor-promoting, phenotypic and functional “B-regulatory cells” (Bregs) in the TME and draining lymph nodes (LNs). Genetic and cell culture experiments indicate that mutant KRAS, by evoking secretion of specific factors, induces Breg development from naïve splenic B cells. Remarkably, SHP2i, acting directly in B cells, blocks Breg development in vitro and in vivo. Moreover, B cell-specific Ptpn11-KO has direct anti-tumor effects. Flow cytometry and immunostaining studies revealed Breg cell expansion in tumor-infiltrated mediastinal lymph nodes (meLNs), accompanied by altered lymph node architecture and altered distribution of B cells between tumors and draining meLNs. Treatment with SHP2i or selective Ptpn11 deletion in B cells restored meLN integrity, even in the presence of KP tumor cell infiltration, and rebalanced B cell distribution. Studies with cell-specific drug resistant mice show that SHP2i action in B cells is required for these effects. Our results provide new insight into the role of tumor-associated B cells and SHP2i in KRAS mutant lung cancer and provide an experimental framework for deconvolving the compartment-specific effects of other targeted therapies in the TME. Citation Format: Benjamin G Neel, Yi Ban, Yingzhuo Liu, Kwok-kin Wong. Deconvolving the cell-specific actions of SHP2 inhibitors in the lung cancer tumor microenvironment reveals requirement for SHP2 in B-regulatory cell development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A018.