Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy

项目总结

PROJECT SUMMARY The majority of patients with solid malignancies undergo chemotherapeutic regimens either in the adjuvant or neoadjuvant setting. Response to chemotherapy is not solely dependent upon the genomic aberrations present within tumors, as it is also contingent upon the infiltration and effector function of cytotoxic lymphocytes, based upon the strong clinical association of CD8+ T cell infiltration with response rates in multiple carcinomas, and supporting evidence of a functional role from implantable mouse tumor models. Enhancing the CD8+ T cell response during chemotherapy therefore has the potential to improve pathologic complete response rates and extend patient survival. We have recently demonstrated using a transgenic mouse model of mammary carcinoma that tumor-associated macrophages abrogate the CD8+ T cell-dependent response during chemotherapy. In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of interleukin 10 within tumors, and IL10 receptor (IL10R) blockade phenocopies the effects of macrophage antagonists during a chemotherapeutic response. While interleukin 10 does not directly suppress CD8+ T cell proliferation or function, we observe increased infiltration of intratumoral dendritic cells and expression of interleukin 12 following treatment with macrophage antagonists in combination chemotherapy. We therefore hypothesize that interleukin 10 suppresses activation of dendritic cells following chemotherapy-induced cell death, thereby preventing reactivation of intratumoral CD8+ T cells and offering a tractable target for improving immune responses during chemotherapy. To test these hypotheses we propose the following specific aims: Determine the functional significance of intratumoral dendritic cell activation in regulating response to chemotherapy following IL10R blockade; determine the functional contribution of intratumoral versus recruited CD8+ T cells in mediating response to chemotherapy following IL10R blockade; and compare durability of anti-tumor immune responses following IL10R blockade and chemotherapy in combination with immune-checkpoint blockade versus co- stimulatory agonists.