The Role of Autophagy in Tumor Immunology and Vasculature

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

Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

The rising success of cancer immunotherapy has produced immense interest in defining the clinical contexts that may benefit from this therapeutic approach. To this end, there is a need to ascertain how the therapeutic modulation of intrinsic cancer cell programs influences the anticancer immune response. For example, the role of autophagy as a tumor cell survival and metabolic fitness pathway is being therapeutically targeted in ongoing clinical trials that combine cancer therapies with antimalarial drugs for the treatment of a broad spectrum of cancers, many of which will likely benefit from immunotherapy. However, our current understanding of the interplay between autophagy and the immune response remains incomplete. Here, we have evaluated how autophagy inhibition impacts the antitumor immune response in immune-competent mouse models of melanoma and mammary cancer. We observed equivalent levels of T cell infiltration and function within autophagy-competent and -deficient tumors, even upon treatment with the anthracycline chemotherapeutic doxorubicin. Similarly, we found equivalent T cell responses upon systemic treatment of tumor-bearing mice with antimalarial drugs. Our findings demonstrate that antitumor adaptive immunity is not adversely impaired by autophagy inhibition in these models, allowing for the future possibility of combining autophagy inhibitors with immunotherapy in certain clinical contexts

Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis

Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia

An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor T cell responses or drive tumor growth.

Neoantigens are critical targets of anti-tumor T cell responses. The ATLAS{trade mark, serif} bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in E. coli, pulsing autologous dendritic cells in an ordered array, and testing the patient\u27s T cells for recognition in an overnight assay. Profiling of T cells from lung cancer patients revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise-protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well-tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T cell responses, with immune responses to 99% of the vaccinated peptide antigens