Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression

Abstract

Mitochondrial dynamics can regulate Major Histocompatibility Complex (MHC)-I antigen expression by cancer cells and their immunogenicity in mice and in patients with malignancies. A crucial role in the mitochondrial fragmentation connection with immunogenicity is played by the IRE1α-XBP-1s axis. XBP-1s is a transcription factor for aminopeptidase TPP2, which inhibits MHC-I complex cell surface expression likely by degrading tumor antigen peptides. Mitochondrial fission inhibition with Mdivi-1 upregulates MHC-I expression on cancer cells and enhances the efficacy of adoptive T cell therapy in patient-derived tumor models. Therefore mitochondrial fission inhibition might provide an approach to enhance the efficacy of T cell-based immunotherapy.

The role of mitochondrial dynamics in disease

“…Many tumors exhibit fragmented mitochondria with upregulated DRP1 and decreased expression levels of MFN1 and MFN2 255 in ovarian cancer, 256 HCC, 257 lung cancer, 258 colon cancer, 259 breast cancer, 252 neuroblastoma, 260 and glioblastoma, 253 which are correlated to the metastatic potential of cancer cells. Increased DRP1 or DRP1‐Ser616 phosphorylation levels can prevent apoptosis, change cellular metabolism, induce immune escape, sustain cell cycle and proliferation in tumor cells, and ultimately promote the occurrence and development of tumors 10,261–263 . Thus, DRP1 inhibition may decrease tumor cell proliferation and invasion and is supported in several tumor models treatment with DRP1 inhibitor, such as Mdivi‐1, vemurafenib, Drpitor1, chloroquine, and isorhamnetin (Table 3), 252,264–267 indicating that DRP1 inhibition is a potential therapeutic approach for tumors.…”

Roles of Mitochondria in Oral Squamous Cell Carcinoma Therapy: Friend or Foe?

“…Interestingly, inhibiting mitochondrial fission could facilitate immunotherapy in TSCC. Specifically, on one hand, reduced mitochondrial fission directly increased the membrane expression of major histocompatibility complex-I in TSCC; on the other hand, reduced mitochondrial fission decreased the production of ROS, which impaired the unfolded protein response of the ER and caused the subsequent suppression of the IRE1α–XBP-1s–TPP2 axis, resulting in increased levels of major histocompatibility complex-I [ 14 ].…”

“…Moreover, mitochondrial ROS (mtROS) can also induce cytochrome C (Cyt C) release by opening the mitochondrial permeability transition pore (mPTP), which causes the apoptosis of OSCC cells [ 13 ]. Interestingly, mitochondrial fission can also boost the production of mtROS and Cyt C [ 14 , 15 ]. However, other characteristics of mitochondria can cause therapeutic resistance [ 16 , 17 ].…”

Controllable mitochondrial aggregation and fusion by a programmable DNA binder

“…21 Excessive ssion are closely related to tumors. 22,23 Traditional mito-therapeutic strategy is normally based on modulating the expression of fusion proteins, which requires either delicate gene engineering process or screening of organic molecules. 24,25 Recently, Wang and coworkers reported another approach for the direct induction of mitochondrial fusion based on host-guest supramolecular assembly, which coins the articial manipulation of mito-fusion as an alternative therapeutic strategy.…”