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 In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of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.
We have found that production of the cytokine interleukin 10 by macrophages within mammary tumors reduces the capacity of those tumors to respond to chemotherapy. Determining how interleukin 10 mediates this effect will improve our ability to monitor patient responses in ongoing clinical trials therapeutically targeting macrophages, and offer insights into new therapeutic strategies to improve the immune response against cancer.
| de Mingo Pulido, Álvaro; Gardner, Alycia; Hiebler, Shandi et al. (2018) TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer. Cancer Cell 33:60-74.e6 |
| Gardner, Alycia; Ruffell, Brian (2018) moDCs, Less Problems. Immunity 48:6-8 |
| Pilon-Thomas, Shari; Ruffell, Brian (2016) Tipping the Balancing ACT. Cancer Cell 30:367-368 |
| Juric, Vladislava; Ruffell, Brian; Evason, Kimberley J et al. (2016) Monocytes promote liver carcinogenesis in an oncogene-specific manner. J Hepatol 64:881-90 |
| de Mingo Pulido, A; Ruffell, B (2016) Immune Regulation of the Metastatic Process: Implications for Therapy. Adv Cancer Res 132:139-63 |
| Gardner, Alycia; Ruffell, Brian (2016) Dendritic Cells and Cancer Immunity. Trends Immunol 37:855-865 |
| Ruffell, Brian; Coussens, Lisa M (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27:462-72 |
| Shiao, Stephen L; Ruffell, Brian; DeNardo, David G et al. (2015) TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer Immunol Res 3:518-25 |
