The indoleamine 2,3 dioxygenase pathway drives intratumoral B cell maintenance

Abstract

AbstractB cells have been implicated as central regulators of immune responses in settings as diverse as mammalian pregnancy, mucosal tolerance, chronic infection states, autoimmunity, and the tumor microenvironment. Despite the established importance of B cells in these environments, the mechanisms by which B cells are maintained in these contexts remain undefined. Here, we report that IDO1 pathway inhibition with D-1-methyl-tryptophan (D-1MT) and linrodostat significantly decreases tumor infiltrating B (TIL-B) cells in a preclinical model of melanoma. Single cell RNA sequencing (scRNAseq) of murine melanoma demonstrate TIL-B cells are heterogeneous but primarily express markers consistent with an immune stimulatory phenotype. D-1MT decreases splenic B cells and bone marrow derived B cell precursors in tumor-bearing mice, suggesting that IDO1 pathway inhibition impedes B cell maturation. D-1MT decreases intratumoral myeloid derived suppressor cells (MDSCs), which are essential for maintenance of TIL-B cells. Unlike D-1MT, genetic deletion of tumor Ido1 does not impact TIL-B or MDSC numbers. In human solid tumors, intratumoral IDO1 expression consistently associates with high expression of a pan-B cell gene signature, and in patients with melanoma, scRNAseq analysis of tumor samples revealed most TIL-B cells express IDO1. Collectively, our data reveal the impact of pharmacologic IDO1 inhibition on B cells, which may have therapeutic implications for patients with solid tumors by informing the design of future oncology clinical trials.