The Role of Autophagy in Tumor Immunology—Complex Mechanisms That May Be Explored Therapeutically

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The Role of Autophagy in Tumor Immunology—Complex Mechanisms That May Be Explored Therapeutically



Introduction
According to the Cancer Immune Edition hypothesis, tumor and immune cell interactions go through three phases: elimination, equilibrium, and evasion. During cancer development, the immune system recognizes molecular changes in transformed cells and eliminates most or all of them, avoiding tumor progression. Genetic alterations that cause cell transformation generate neoantigens for immune recognition, leading to T lymphocyte activation, which can prevent tumor outgrowth, through cytotoxic activity and interferon-gamma (IFN-γ) signaling (1, 2). At the same time, less immunogenic mutations or mutations that lead to loss of the antigen recognized by the immune system allow tumor cells to escape from elimination mechanisms. As genetic alterations accumulate, generating oncogenes and preventing the expression of tumor-suppressor genes, transformed cells gain proliferative advantages, and again escape immunosurveillance, leading to tumor progression (3, 4).

The interplay between tumor and other cells composing the tumor microenvironment (TME) is determinant for tumor growth, maintenance, metastasis, and response to therapy. TME is composed of stromal cells (fibroblasts, pericytes, mesenchymal and endothelial cells), extracellular matrix (ECM), and immune cells, such as natural killer (NK) cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and T and B lymphocytes. During cancer progression, tumor cells display genetic and phenotypic diversity, changing cellular metabolism and, consequently, the TME (5, 6).

Generally, TME displays low levels of oxygen and nutrients, and high production of reactive oxygen species (ROS), crucial factors for autophagy activation. Autophagy is a natural cellular survival process, usually activated to maintain cellular homeostasis (7, 8). Despite that, recent studies have suggested that autophagy is also important for cancer development and progression, neurodegenerative and infectious diseases, once it can affect immune cells and modulate immune responses (9–11).

In this review, we will present the major mechanisms by which the immune system interferes in the TME, and how autophagy can influence it. Then we will focus on the modifications of cancer immune responses in TME influenced by autophagy and how it can affect cancer therapy.




https://www.frontiersin.org/articles/10 ... 03661/full