Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Experimental Pathology

First Advisor

Bosenberg, Marcus

Abstract

Melanoma is the most aggressive skin cancer and is estimated to have caused 7180 deaths in the United States in 2021. Immune checkpoint inhibitors have revolutionized melanoma treatment over the past decade and dual therapy with anti-PD-1 and anti-CTLA4 inhibitors is currently the standard of care for advanced melanoma. Despite the success of this treatment regimen, resistance remains a significant clinical challenge. Many tumors either do not respond to checkpoint inhibition or develop resistance and ultimately patients experience disease progression. Options for these patients are limited and there is a critical need for new therapies to adequately treat anti-PD1 non-responders. The tumor microenvironment (TME) plays an important role in determining the efficacy of various treatments and tumors with poor T cell infiltration and an abundance of immunosuppressive myeloid elements have poor responses to traditional checkpoint blockade. Myeloid and dendritic cells within the TME can modulate checkpoint resistance by either supporting or suppressing adaptive immune responses. Tumor-associated macrophages (TAMs) in particular play a critical role in setting the immune activation state of the TME. Tumor driven dysfunction or co-optation of myeloid cells results in immunosuppression and a TME that is insensitive to checkpoint blockade. Therefore, we hypothesized that by targeting the myeloid compartment in the tumor, we can repolarize the TME towards a more hospitable environment for T cell recruitment and activation. Using a mouse model of anti-PD1 resistant melanoma, this thesis shows that modulating the myeloid compartment in combination with checkpoint blockade results in complete tumor regression. CD40 is a pleotropic costimulatory molecule that stimulates dendritic cell maturation and antigen presentation, as well as proinflammatory macrophage activation. CSF1R is a macrophage survival cytokine that promotes a pro-tumorigenic TAM phenotype. In this thesis dissertation, I demonstrate that triple therapy with a CD40 agonistic antibody, CSF1R blocking antibody and anti-PD1 can overcome anti-PD1 resistance in T-cell excluded tumors. The efficacy of the triple therapy is primarily CD40-agonist driven and shows a similar systemic cytokine profile in humans as in our murine models. Furthermore, through novel, functional dendritic cell cytokine profiling, we identified a specific CCL22+CCL5+ IL-12-secreting dendritic cell (mregDC) subset as the primary target of treatment. T cells are the ultimate effectors of the triple therapy combination, and the mregDC subset likely acts to enhance T cell activation and recruitment. In summary, this work shows how modulating innate immunity, and specifically the myeloid compartment, can be a powerful tool in the immunotherapy toolkit. Combining myeloid-based innate immune activation in order to enhance adaptive immunity is a viable strategy to overcome resistance to checkpoint blockade.

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