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 In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
4R00CA185325-02
Application #
9031228
Study Section
Special Emphasis Panel (NSS)
Program Officer
Welch, Anthony R
Project Start
2015-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Gardner, Alycia; Ruffell, Brian (2018) moDCs, Less Problems. Immunity 48:6-8
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