Abstract
Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is important to resolve these issues to predict the use of autophagy inhibitors in combination with immunotherapies in clinical settings.
Highlights
While initially considered as a disease of cells with deregulated gene expression, cancer progression is considered to be largely influenced by the tumor microenvironment
Based on our data showing that targeting autophagy restores tumor cell susceptibility to natural killer (NK)-mediated lysis in vitro, we investigated whether blocking autophagy reduces tumor growth in an NK-dependent manner
In the context of naive T cells, it has been reported that tumor-derived metabolite lactate selectively inhibits FAK family–interacting protein of 200 kDa (FIP200; known as RB1CC1) in naive T cell leading to autophagy deficiency, apoptosis and poor antitumor immunity in ovarian cancer patients, and tumor-bearing mice [93]
Summary
While initially considered as a disease of cells with deregulated gene expression, cancer progression is considered to be largely influenced by the tumor microenvironment. Effector immune cells infiltrating tumors, notably T lymphocytes and natural killer (NK) cells mediating adaptive and innate immunity, respectively, are basically the major immune cells able to kill cancer cells in the tumor microenvironment [3] These immune effectors are recruited to the tumor site, they are exhausted and their antitumor functions are often downregulated in response to microenvironmental factor such as hypoxia. Hypoxia is resulted from decrease in O2 partial pressure in arterial blood, and from pathological conditions, such as anemia (anemic hypoxia), which restrict the ability of blood vessel to carry O2 It can be generated from dramatic decrease in tissue perfusion or defect of cells to use O2.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
