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The Role of Autophagy in Tumor Immunology and Vasculature

  • Author(s): Starobinets, Hanna Sonia
  • Advisor(s): Werb, Zena
  • et al.
Abstract

Cancer therapy of the last hundred years has mainly aimed to quell cancer cells’ intrinsic abnormalities. Although chemotherapies and targeted therapies have been successful at controlling the disease in the short term, even the best outcomes have largely been long-term remissions. Cancer therapy of the 21st century has turned much of its attention to manipulating the processes that occur in the tumor microenvironment. This approach aims to undermine cancer’s ability to hijack its local and distant host environments to support its own growth and progression.

Therapies targeting immune and vascular components of the tumor microenvironment have met with immense success in improving the prognosis of the most devastating forms of cancer such as metastatic melanoma and glioblastoma. Immune therapies unleashing the full potential of the body’s anti-cancer immune response are beginning to achieve what clinicians are tentatively labeling as complete cures: a subset of patients with metastatic melanoma have exhibited a survival curve plateau that has already surpassed 10 years in duration (1). Vascular therapies aiming to destroy tumor blood vessels and cut off supply of critical nutrients hit a roadblock until they pivoted their focus toward altering the vasculature in a way to improve drug delivery to tumors, an approach that is showing early signs of promise (2). These and other therapies designed to combat the tumor as a whole and transforming the landscape of preclinical and translational cancer research. Much effort is now devoted to defining and disrupting the many poorly understood cell interactions with the tumor microenvironment with the aim to develop single and combination therapies with durable responses across all patients and all tumor types.

Here, I investigate the effects of autophagy inhibition on the immune and vascular systems in preclinical immune competent models of cancer. Autophagy, or “self-eating,” is a cellular process involved in homeostatic health and stress survival that has been implicated in tumorigenesis, and thus has gained considerable interest as a target in various ongoing cancer clinical trials. I find that inhibiting autophagy does not impact the anti-cancer T cell response in melanoma or breast cancer models, but alters tumor vascular function within a triple-negative breast tumor microenvironment. My work raises the enticing possibility of combining autophagy inhibition with chemotherapy and/or immune therapy to improve drug delivery and clinical outcomes. This combination approach would weaken cancer cells dependent on autophagy to survive the numerous stresses of the tumor microenvironment, while delivering a second hit of a chemical or immune attack. Many of my findings are in direct contradiction to existing published literature, suggesting that these dynamic and context-specific processes require deeper mechanistic understanding to determine appropriate clinical uses.

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