Mitochondrial Proteins as Source of Cancer Neoantigens

Abstract

In the past decade, anti-tumour immune responses have been successfully exploited to improve the outcome of patients with different cancers. Significant progress has been made in taking advantage of different types of T cell functions for therapeutic purposes. Despite these achievements, only a subset of patients respond favorably to immunotherapy. Therefore, there is a need of novel approaches to improve the effector functions of immune cells and to recognize the major targets of anti-tumour immunity. A major hallmark of cancer is metabolic rewiring associated with switch of mitochondrial functions. These changes are a consequence of high energy demand and increased macromolecular synthesis in cancer cells. Such adaptations in tumour cells might generate novel targets of tumour therapy, including the generation of neoantigens. Here, we review the most recent advances in research on the immune response to mitochondrial proteins in different cellular conditions.

Keywords: T cell response; cancer neoantigens; mitochondria; mtDNA mutations; post translational modifications.

Figure 1

Mitochondrial-derived antigens and possible mechanisms promoting their immunogenicity. In tumour cells neo-antigens can be generated via mutations of mitochondrial DNA and different modifications compared to normal cells. The uptake of mitochondria and mitochondrial debris by dendritic cells may involve tunnelling nanotubes (TNTs), extracellular vesicles (EVs), and mitochondria-derived vesicles (MDVs). Tumour antigens (red dot) are presented to specific T cells, which in turn expand and acquire the capacity to recognize tumour cells. Mitochondrial proteins released in the cytoplasm may be processed by proteasome, translocated into the endoplasmic reticulum, and presented by MHC class I molecules. Autophagy is involved in the presentation of endogenous antigens by both MHC class I and class II molecules. Accordingly, mitophagy, a form of macro autophagy that selectively degrades damaged mitochondria, might play a role in presentation of mitochondrial antigens. Other components of mitochondria from tumour cells, including lipids and metabolites, could also represent antigens stimulating specific T cells. However, experimental evidence is still lacking.