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Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE192515 | GEO | 2023/08/25

REPOSITORIES: GEO

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Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer.

Project description:Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

| S-EPMC10517947 | biostudies-literature

Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer (bulk RNA-seq)

Project description:We utilized bulk RNA sequencing to assess intrinsic differences between wildtype and autophagy-defective (Atg16l1 deleted) AKPS colorectal cancer organoids in both untreated and IFN gamma treated conditions. AKPS mutations consist of loss-of-function in tumor suppressors Apc, Trp53, Smad4, and gain-of-function in oncogenic Kras(G12D).

2023-08-28 | GSE192513 | GEO

Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer (single cell RNA-seq)

Project description:We utilized 10X single cell RNA sequencing to investigate in murine liver how Atg16l1 deletion in AKPS colorectal cancer organoids impacted phenotypic programming of organoid cells and myeloid cells in the tumor microenvironment. Atg16l1 KO and Wt cells were inoculated into the liver of NSG mice via HTV injection. Tumors were harvested following ~3 weeks of growth and live Calcein blue+ 7ADD– cells were sorted into tumor (eGFP+CD45–) and immune (eGFP–CD45+) cells.

2023-08-28 | GSE192514 | GEO

Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

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.

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Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

Project description:Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

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Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer (bulk RNA-seq)

Project description:Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer (bulk RNA-seq)

| PRJNA791686 | ENA

Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer (single cell RNA-seq)

Project description:Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer (single cell RNA-seq)

| PRJNA791690 | ENA

GOLM1 suppresses autophagy-mediated anti-tumor immunity in hepatocellular carcinoma.

Project description: Not available

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Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2).

Project description:Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. WhileT cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell inflamed tumor microenvironment are not fully understood. We conducted an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment(TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified EPHA2 as a candidate tumor intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that PTGS2, the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGF? and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2-PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a novel therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2-TGF?-PTGS2 pathway inhibitors with anti-tumor immunotherapy, and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.

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Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer.

Project description:Although immune checkpoint blockade (ICB) improves clinical outcome in several types of malignancies, pancreatic ductal adenocarcinoma (PDA) remains refractory to this therapy. Preclinical studies have demonstrated that the relative abundance of suppressive myeloid cells versus cytotoxic T cells determines the efficacy of combination immunotherapies, which include ICB. Here, we evaluated the role of the ubiquitin-specific protease 22 (USP22) as a regulator of the immune tumor microenvironment (TME) in PDA. We report that deletion of USP22 in pancreatic tumor cells reduced the infiltration of myeloid cells and promoted the infiltration of T cells and natural killer (NK) cells, leading to an improved response to combination immunotherapy. We also showed that ablation of tumor cell-intrinsic USP22 suppressed metastasis of pancreatic tumor cells in a T-cell-dependent manner. Finally, we provide evidence that USP22 exerted its effects on the immune TME by reshaping the cancer cell transcriptome through its association with the deubiquitylase module of the SAGA/STAGA transcriptional coactivator complex. These results indicated that USP22 regulates immune infiltration and immunotherapy sensitivity in preclinical models of pancreatic cancer.

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