Date of Award

Fall 8-23-2022

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Patricia Pioli

Abstract

The high immunogenicity of melanoma tumors makes these malignancies an attractive target for immunotherapeutic treatment, as evidenced by the success of ipilimumab and nivolumab. However, most immunotherapeutic approaches have had limited success, partly due to the suppression of innate and adaptive immune responses by tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). TAM redirection may relieve immunosuppression in the TME, directly inhibiting melanoma growth and potentially enhancing the efficacy of additional targeted and immuno-therapies.

We have shown that synthetic oleanane triterpenoid CDDO-Me (or C-Me) enhances immune activation in the melanoma TME by reprogramming TAMs from immunosuppressive to immunostimulatory. CDDO-Me is an anti-inflammatory drug developed for the prevention and treatment of cancer. While most studies have focused on defining CDDO-Me-mediated effects on tumor cell growth and activation, little is known about the influence of CDDO-Me on immune cells in melanoma TME.

Using a human melanoma tri-culture model, we show that CDDO-Me significantly attenuates the production of IL-6 and CCL2, which mediates TAM recruitment. Inhibition of CCL2 has also been shown to substantially reduce angiogenesis and melanoma tumor growth, while IL-6 signaling drives proliferation, survival, and invasiveness of tumor cells.

Furthermore, our recent studies in an autochthonous mouse model of melanoma driven by oncogenic BRAFV600E and loss of the tumor suppressor Pten demonstrate that CDDO-Me significantly reduces primary and total tumor burden. Dual treatment of BRAF inhibitor, a small molecule inhibitor of a serine/threonine kinase in the MAPK pathway (BRAFi, PLX4720) with CDDO-Me remodels the TME, potentially leading to inhibition of acquired resistance to BRAFi. Our work shows the immune modulatory effect of CDDO-Me in melanoma and highlights its ability to reshape the TME by controlling immune cell migration, polarization, and protein production.

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