Mitochondrial stress promotes immunosuppressive potential of myeloid subsets in tumors - ABSTRACT The immunosuppressive tumor microenvironment (TME) orchestrated by advanced malignancies represents a key driver for tumor progression and a challenge for the successful development of curative immunotherapies. Multiple pro-inflammatory processes active in the TME induce chronic myelopoiesis and subsequent expansion of highly immunosuppressive myeloid cells, including Myeloid-derived suppressor cells (MDSC) subsets, Tumor- associated macrophages (TAM), and Dendritic cells (DC). To date, however, the approaches to clinically block the regulatory effects of myeloid cells in tumors are limited to myelosuppressive agents or inhibitors that are only partially effective. Thus, alternative strategies to overcome the immunosuppressive and pro-tumorigenic actions of myeloid cells in cancer are expected to have a significant clinical impact. Infiltration of myeloid cells into tumors makes them exposed to stress conditions, including hypoxia, nutrient deprivation, and elevated reactive oxygen and nitrogen species, which trigger overactivation of endoplasmic reticulum (ER) stress. Our recent manuscripts demonstrated that maladaptive signaling by major arms of the ER stress responses, PERK and Chop, impaired anti-cancer immunity by intrinsically altering the metabolic and functional activity of myeloid cells in tumor beds. Notably, our new preliminary results in tumor-infiltrating myeloid cells indicate a potential crosstalk between ER stress response signals and the activation of mitochondrial unfolded protein response (UPRmt), a process that ultimately controls mitochondrial homeostasis under stress. Thus, we hypothesize that the chronic overactivation of PERK→Chop provokes detrimental UPRmt in tumor-linked myeloid cells, which results in a program that allows mitochondrial adaptation to stress and sustains immune evasion. Also, we postulate that therapeutic targeting of UPRmt driver LonP1 limits immunosuppressive myelopoiesis, primes protective anti-tumor T cell responses, and augments the effectiveness of cancer immunotherapy. Thus, proposed studies will unearth for the first time a mechanistic link between maladaptive ER stress and UPRmt as a central metabolic inhibitory system in tumor- related myeloid cells, while outlining new strategies to effectively reprogram immunosuppressive myelopoiesis and to enhance the effects of immunotherapy. We propose the following Specific Aims: Aim 1. Determine the role of the activation of the PERK→Chop axis in the induction of UPRmt in tumor-associated myeloid cells. Aim 2. Elucidate the role of UPRmt driver LonP1 in the regulatory activity of tumor-linked myeloid cells. Aim 3. Evaluate whether inhibition of LonP1 augments the effectiveness of cellular- and checkpoint-based immunotherapies in tumor-bearing hosts.
