Date of Award

6-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Liza Makowski, PhD

Committee

Kevin W. Freeman, PhD; Evan S. Glazer, MD, PhD; Yi Lu, PhD; Paul G. Thomas, PhD

Keywords

Antigen Presentation, Breast Cancer, Combination, Immunotherapy; Myeloid Cells, Protein Kinase C

Abstract

Checkpoint immunotherapy unleashes T cell antitumor potential which has revolutionized cancer treatment showing unprecedented long-term responses. However, most patients do not respond to immunotherapy which often correlates with a dysfunctional or immunosuppressive myeloid compartment. Immunosuppressive myeloid cells comprise Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) and can suppress T cells via production of immunosuppressive factors. Conversely, efficient cytotoxic T cell priming is dependent on the ability of antigen-presenting cells (APCs), mainly conventional dendritic cells (cDCs) and macrophages, to present or cross-present tumor antigens to T cells. Thus, targeting immunosuppressive myeloid cells while simultaneously enhancing APCs represents a promising strategy that, when combined with immunotherapy, may result in long-lasting protective immunity. In this dissertation, we first investigated the effect of protein kinase C (PKC) agonist PEP005 on MDSC expansion, differentiation, and recruitment to the tumor microenvironment. We found that PKC agonists decreased MDSC expansion from the bone marrow and induced MDSC differentiation to an APC-like phenotype via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. PKC agonists blunted MDSC suppressive activity and enhanced MDSC cross-priming capacity both in vitro and in vivo. Concurrently, PKC agonists favored the expansion of cross-presenting cDC1 at the expense of cDC2 and plasmacytoid DCs (pDC). Lastly, combination of PKC agonism with agonistic CD40 mAb, a form of innate immunotherapy, resulted in a reduction in tumor growth with a significant increase in intratumoral activated CD8+ T cells in a syngeneic breast cancer mouse model. This work proposes a novel promising strategy to simultaneously target MDSCs and promote APC function that may have highly impactful clinical relevance in cancer patients.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0002-4793-0120

DOI

10.21007/etd.cghs.2022.0613

Additional Files
2022-012-Chaib-DOA.pdf (186 kB)
Declaration of Authorship
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