The B cell adapter for PI3K (BCAP) promotes M2 macrophage phenotype and safeguards tumors from immune surveillance

Abstract

Abstract The tumor microenvironment is a complex milieu consisting of different populations of infiltrating immune cell populations. Macrophages and DCs within the tumor microenvironment are vital in priming naïve T cells within tumors and tumor draining lymph nodes and collectively guide responses to various immunotherapies. Macrophages can exist in both pro-inflammatory (M1) state and produce IL-6, IL-12, TNF-α and ROS to promote anti-tumor responses, and reparative (M2) state that support angiogenesis and secrete IL-10 and TGF-β favoring tumor growth. We have previously identified BCAP as an adapter that links TLRs to PI3K/Akt activation and negatively regulates inflammatory responses. Recent work has shown a critical role of BCAP in promoting the transition of M1 macrophages to M2 phenotype. Since tumor associated macrophages (TAMs) in their M2 state have tumor promoting roles, we wanted to investigate if deficiency of BCAP could drive anti-tumor responses. BCAP null mice with implanted MC38 tumors had significantly reduced tumor burden and higher infiltration of leukocytes. This included higher presence of CD4+ and CD8+ T cells as well as macrophages and inflammatory monocytes in the tumor microenvironment. We are currently investigating macrophage and T cell intrinsic role of BCAP on tumor growth. Finally, to understand the molecular events leading to differential tumor progression in BCAP deficient condition, we will interrogate the transcriptional profile of tumor infiltrating myeloid and lymphoid cells at different stages of tumor growth and examine the potential role of MyD88 and PI3K/Akt signaling in myeloid cells in influencing BCAP dependent tumor growth. Supported by grant from NIH (R01 AI113125)