Introduction: CD8+ tumor-infiltrating T lymphocytes (TIL) in the tumor microenvironment (TME) are unable to kill their tumor targets due to tumor cell & regulatory immune cell-mediated suppression. Poor metabolite availably has also been found to negatively impact TIL, as T cells have high energetic demands that are not met in the TME due to competition with surrounding tumor cells. Consequently, tumor growth is allowed to progress as TIL becomes exhausted & dysfunctional. Immunotherapy, such as PD-1 checkpoint blockade, has been highly successful at treating many types of human cancer, but the majority of patients do not respond for reasons which are still unclear. Cancer cells have been shown to have heterogeneous, dysregulated metabolism, which could be a barrier to immunotherapy. Therefore, we hypothesize that TIL dysfunction & thus resistance to immunotherapy is driven in part by metabolic insufficiency, & either improving TIL metabolism or normalizing tumor metabolism can lower the barrier to immunotherapy to improve cancer outcomes.
Methods: Metabolic capacity was measured using flow cytometry & flux analysis in murine and human tumor samples. T cell reprogramming was performed by retroviral transduction on antigen-specific T cells before adoptive transfer into tumor-bearing mice. TME reprogramming was performed on tumor-bearing mice that were treated with metformin every other day & anti-PD1 3x weekly.
Results: We found that exhausted TIL exhibit a profound loss of functional mitochondria. This is due in part to repression of the transcriptional co-activator PGC1α resulting in suppressed mitochondrial biogenesis. Enforcing mitochondrial biogenesis in T cells not only led to increased mitochondrial mass, but improved TIL functionality, decreased tumor burden, & increased survival in mouse melanoma. To understand the effects of T cell-extrinsic metabolic insufficiency, we explored the TME factor hypoxia on TIL function. CD8 T cells function poorly in hypoxia, thus causing a possible barrier to function. We first compared the energetics of different murine tumor lines & found that tumor cells with a more deregulated oxygen metabolism (i.e. those that created more hypoxia), tended to be resistant to immunotherapy. When tumor cells were treated with metformin in vivo, a compound that decreases tumor mitochondrial oxygen consumption, overall tumor hypoxia was decreased. Metformin alone did not improve tumor clearance, but when used in combination with PD-1 checkpoint blockade, TIL effector function was dramatically increased, 80% of mice experienced tumor regression, & 70% of mice became tumor-free.
Conclusions: TIL metabolic insufficiency may provide rationale as to why some patients do not benefit from PD-1 monotherapy. Decreasing TIL intrinsic or extrinsic metabolic insufficiency may improve upon existing cancer immunotherapies, as well as allow for development of targeted therapies to greatly improve cancer outcomes.
Citation Format: Nicole E. Scharping, Ashley V. Menk, Greg M. Delgoffe. The metabolic requirements for effective immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 632.