Project description:Here we demonstrate that inactivation of the essential autophagy genes, Atg5, Atg14, or Atg16L1 results in tumour rejection. Despite a significant reduction in the total number of CD8+ tumour infiltrating lymphocytes (TILs), loss of Atg5 causes a profound shift toward IFNg and TNF producing effector memory cells. Consistent with this, adoptive transfer with Atg5-/- T cells promotes tumour control. Mechanistically, CD8+ T cells lacking autophagy exhibit enhanced glucose metabolism resulting in global changes in histone trimethylation and increased transcriptional activation of effector target genes. Restricting glucose is sufficient to suppress autophagy-dependent increases in effector function and reverse alterations in histone trimethylation. These findings identify autophagy as a cell-autonomous negative regulator of CD8+ T cell anti-tumour immunity with implications on T cell-based immunotherapy.
Project description:PRMT1 is known as a regulator of immune function by directly interacting with interferon receptors, methylating STAT1, and promoting B cell and macrophage differentiation by methylating CDK4 or B cell antigen receptor However, the function of PRMT1 as a therapeutic target of cancer remains largely elusive, particularly for its role in cancer immunosurveillance. Here, we performed bulk RNA-seq for CT26, a mouse tumor cell line, after either knocking down of endogeneous Prmt1 or blocking PRMT1 by two specific inhibitors, namely MS023 and GSK3368715.
Project description:The vast majority of colorectal cancer (CRC) patients fail to respond to immune checkpoint inhibitors (ICI). Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve CRC patient outcomes. Here, we demonstrate that transcript levels of the core autophagy gene ATG16L1 are prognostic of poor outcome and predictive of ICI resistance in late-stage CRC. Deletion of Atg16l1 in murine CRC organoids markedly inhibited tumor growth in primary and metastatic niches in syngeneic hosts. ATG16L1 deficiency rendered CRC organoids more responsive to interferon (IFN) signaling and enhanced programmed cell death while decreasing tumor stem-like populations. IFN hypersensitivity consequently promoted cytotoxic anti-tumor immunity in vivo. In IMblaze370, a large phase III clinical trial of anti-PD-L1 in advanced metastatic CRC, low ATG16L1 levels identified patients with increased lymphocyte infiltration and improved outcome in a KRAS mutant setting. This work reveals autophagy as a clinically relevant immunosuppressive mechanism in CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.