Degree Name

Master of Science

Document Type

Thesis

Date Created

5-1-2020

Department

College of Natural and Health Sciences, Biological Sciences, Biological Sciences Student Work

Abstract

Immunotherapies that augment Type I immunity show robust responses in diffuse blood cancers yet remain relatively ineffective in breast and other solid tumor malignancies. Breast tumor resistance to immunotherapies is associated with polarization towards pro-tumor Type 2 immunity, as well as the expansion of a myeloid derived suppressor cell (MDSC) population that inhibits Type 1 T helper (Th) and CD8+ cytotoxic T cells. Does polarization toward Type 3 immunity play a role in mammary tumor formation? This question had not been investigated prior to these studies despite established relationships between MDSCs and Type 3 Th cells in other inflammatory pathologies. Therefore, we investigated involvement of Type 3 Th cells (Th17 and Th22) and their association with expanding MDSC populations in the 4T1 mouse mammary carcinoma model. When evaluated at multiple time points after 4T1 injection (days 7, 14, 21, and 28), tumor infiltration of Th17 and Th22 cells was first detected at d 14, and Th17 populations declined after this time while Th22 remained unchanged. In peripheral organs, Th17 increased by d 7 before declining, while Th22 were not elevated until later times. Only Th17 and MDSC expansion in the bone marrow were positively correlated, suggesting further that Th17 and Th22 are functionally distinct lineages and that MDSCs may play a role in Th17 fate determination in breast cancer. To further address a possible relationship between MDSCs and Type 3 Th cells in mammary carcinoma, we used CRISPR-Cas9 to knock out tumor cell-specific production of interleukin (IL) -6 (IL6-KO), which functions in Th maturation, myelopoiesis, and MDSC recruitment. Tumor-resident Th17, Th22, and MDSCs did not change in IL-6 KO tumors, suggesting a limited role for IL-6 in local recruitment. However, induction of Th22 and MDSCs in peripheral tissues was significantly reduced with IL6-KO tumors, while Th17 cells were increased. These concomitant changes in peripheral Type 3 Th and MDSCs suggests direct functional interactions between these populations, yet additional studies are required to confirm this. To conclude, we identify and characterize a pro-tumor Type 3 Th immune response that accompanies MDSC expansion in a model of metastatic breast cancer. This is important because these populations are associated with reduced efficacy of cancer immunotherapies.

Keywords

MDSC; Th17; Th22; Th1/17; Th1; 4T1 mammary carcinoma

Comments

Spring 2020 Graduate Dean's Citation for Outstanding Thesis, Dissertation, and Scholarly Project

Rights Statement

Copyright is held by the author.

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