Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth

Abstract

Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.

An asymmetrically dimethylarginated nuclear 90 kDa protein (p90aDMA) induced by interleukin (IL)-2, IL-4 or IL-6 in the tumor microenvironment is selectively degraded by autophagy

“…2B and D). A growing body of evidence indicates that similar elimination of signaling molecules play key roles in autophagy-regulated immune responses (53)(54)(55)(56)(57). For instance, microglial autophagy plays an important role in the clearance of extracellular Aβ (β-amyloid) fibrils and the regulation of Aβ-induced inflammation, thereby affecting neuronal viability (53).…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Intracellular antigen presentation via MHC class I molecules is also regulated by the autophagy machinery, because autophagy‐related proteins enhance MHC class I internalization for degradation and thereby diminish antigen display on the cell surface 268. Indeed, in vivo studies have primarily found enhanced CD8 + T cell responses in mice with defective autophagy in antigen‐presenting cells268, 269, 270 A potential mechanism leading to such increased CD8 + T cell expansions is that, in the absence of autophagy, more substrate becomes available for canonical MHC class I loading271 or by decreased endocytosis and degradation of cell surface MHC class I molecules 268. Thus, defective autophagy in skeletal muscle fibers could drive increased MHC class I expression and CD8 + T cell accumulation.…”

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

“…It has been suggested to hold a tumour suppressive function during early tumourigenesis, [20][21][22][23][24][25][26][27] whereas it can also sustain cancer progression. [28][29][30][31][32][33][34][35][36] Increased levels of basal autophagy have been found in a variety of cancer tissues including colorectal cancer (CRC), where autophagy supports tumour growth and confers tumour aggressiveness. 31 Autophagy is inhibited by oncogenic tyrosine kinases (OncTKs) and receptor tyrosine kinases (RTKs) via activation of the PI3K/AKT/mTORC1 and RAS/MAPK signalling.…”

“…[28][29][30][31][32][33][34][35][36] Increased levels of basal autophagy have been found in a variety of cancer tissues including colorectal cancer (CRC), where autophagy supports tumour growth and confers tumour aggressiveness. 31 Autophagy is inhibited by oncogenic tyrosine kinases (OncTKs) and receptor tyrosine kinases (RTKs) via activation of the PI3K/AKT/mTORC1 and RAS/MAPK signalling. 37 In this respect, work from our group and others has shown that induction of autophagy upon pharmacological targeting of OncTKs/RTKs promotes survival.…”