Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis

Abstract

In colorectal cancer patients, a high density of cytotoxic CD8 T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8 T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8 T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.

Epithelial CD80 promotes immune surveillance of colonic preneoplastic lesions and its expression is increased by oxidative stress through STAT3 in colon cancer cells

“…The role of STAT3 in carcinogenesis is controversial: studies have demonstrated that STAT3 can function either as an oncoprotein or a tumor suppressor in the same cell type, depending on the specific genetic background or presence/absence of specific coexisting biochemical defects [44]. In the AOM and the Apc (Min/+) mouse models of colorectal cancer, the deletion of STAT3 in the intestinal epithelial cells reduced early adenoma formation (i.e., oncogenic role) [45, 46]. However, ablation of STAT3 in the later stage of tumor progression significantly increased the invasiveness of the tumors and decreased the survival of the animals (i.e., tumor suppressor role) [45].…”

“…In the AOM and the Apc (Min/+) mouse models of colorectal cancer, the deletion of STAT3 in the intestinal epithelial cells reduced early adenoma formation (i.e., oncogenic role) [45, 46]. However, ablation of STAT3 in the later stage of tumor progression significantly increased the invasiveness of the tumors and decreased the survival of the animals (i.e., tumor suppressor role) [45]. Since low surface expression of CD80 is an immunoescape mechanism of colon carcinoma [47], we speculate that the tumor suppressor role of STAT3 in the later stages of colon cancer progression may be explained by its ability to enhance CD80 expression.…”

Immunotherapy, Inflammation and Colorectal Cancer

“…Although 96% of all CRCs do not develop in the context of pre-existing inflammation, the roles of chronic inflammation, tumor-elicited inflammation, the tumor microenvironment (TME), and partially adaptive immune cells in CRC development, have been established, particularly in the context of their interaction with gut dysbiosis [18][19][20][21][22][23]. Colitis-associated cancer (CAC) is a specific subset of CRC characterized by its implication with inflammation that accounts for 1%-2% of all CRCs [24].…”

Perspectives Regarding the Intersections between STAT3 and Oxidative Metabolism in Cancer

“…However, an opposing report indicated that increased expression of IP3R3 stimulated cancer cell survival by promoting cellular metabolism [ 104 ]. Mice with colon cancer, driven by mutations of the gene encoding β-catenin, undergo a STAT3-dependent increase in aerobic glycolysis and suppression of ETC activity, which are mediated by the upregulated expression of HIF-1α and Myc [ 67 , 105 ]. The mechanism of how STAT3 regulates mitochondrial activity is not yet clear; however, specifically targeting mitochondrial activity is postulated to suppress tumor growth.…”