Role of Mitochondria in Cancer Immune Evasion and Potential Therapeutic Approaches.

Katherine Klein,Meidi Gu,Tugce Ozgen,Roshal R Patel,Dawei Chen,Aarthi Narayanan,Ahmed I Younes,Maria Angelica Cortez,James W Welsh,Kewen He,Hampartsoum B Barsoumian,Sara Mosaffa,Jose Novaes

doi:10.3389/fimmu.2020.573326

Abstract

The role of mitochondria in cancer formation and progression has been studied extensively, but much remains to be understood about this complex relationship. Mitochondria regulate many processes that are known to be altered in cancer cells, from metabolism to oxidative stress to apoptosis. Here, we review the evolving understanding of the role of mitochondria in cancer cells, and highlight key evidence supporting the role of mitochondria in cancer immune evasion and the effects of mitochondria-targeted antitumor therapy. Also considered is how knowledge of the role of mitochondria in cancer can be used to design and improve cancer therapies, particularly immunotherapy and radiation therapy. We further offer critical insights into the mechanisms by which mitochondria influence tumor immune responses, not only in cancer cells but also in immune cells. Given the central role of mitochondria in the complex interactions between cancer and the immune system, high priority should be placed on developing rational strategies to address mitochondria as potential targets in future preclinical and clinical studies. We believe that targeting mitochondria may provide additional opportunities in the development of novel antitumor therapeutics.

Highlights

As much of cells’ metabolic signaling takes place in mitochondria, or is regulated by mitochondrial activities, knowledge of mitochondrial function is critical to the discussion of cancer cell metabolism
They further found that direct activators of mTOR, AMPK, or PGC1a synergistically enhanced the antitumor effects of PD1 blockade therapy. These findings provide a proof of concept for a combinational strategy involving mitochondrial activation agents and PD1 inhibitors for patients with disease that is not responsive to PD1 inhibitors. These findings further suggest that markers of mitochondrial activation such as proliferator-activated receptor g coactivator-1 alpha (PGC-1a) could be useful as biomarkers of the effectiveness of PD1 blockade as antitumor therapy
Because BRAF inhibitors induce PGC-1a, a regulator of mitochondrial biogenesis that in turn causes oxidative phosphorylation (OXPHOS) upregulation [65], combining BRAF inhibitors and phenformin could have reduced the proliferation of BRAFmutant melanoma cells and contribute to tumor regression in that study

Summary

Introduction

As much of cells’ metabolic signaling takes place in mitochondria, or is regulated by mitochondrial activities, knowledge of mitochondrial function is critical to the discussion of cancer cell metabolism. Signaling through PDL1 was found to directly upregulate glycolysis in tumor cells through activating the AKT/mTOR pathway [43], leading to enhanced glucose uptake and lactate production and the expansion and survival of these tumor cells.

Results

Conclusion