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

ABSTRACT: 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.

PROVIDER: EGAS00001005952 | EGA |

REPOSITORIES: EGA

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Clonal deletion of tumor-specific T cells by IFN-g confers therapeutic resistance to combination immune checkpoint blockade

Project description:Combination immunotherapy is being developed with the goal of enhancing anti-tumor immunity. Despite remarkable clinical responses, most patients do not experience complete responses from combination checkpoint blockade treatments. Therefore, a need exists to further explore the mechanisms of resistance to these therapies. Here, we investigate whether tumor burden could be an important factor in determining the treatment outcomes of combination checkpoint blockade. We found that while combined anti-CTLA-4 and anti-PD-1 improves control of established tumors, this combination can paradoxically compromise anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. This paradoxical outcome results from treatment-induced deletion of tumor-specific T cells that is mediated through IFN-γ. Activated tumor-specific T cells express higher levels of IFN-γ receptor and are more susceptible to apoptosis. As a result, combination treatment alters the T cell repertoire landscape, skewing the distribution of T cells toward lower frequency clonotypes. Deficiency of the IFN-γ receptor on immune cells restores anti-tumor activity. Additionally, tumor-specific T cells lacking the IFN-γ receptor demonstrate a significant survival advantage compared to their wild-type counterparts in tumor-bearing mice receiving combination therapy. Finally, we show that combination therapy induces significantly higher levels of IFN-γ in the low versus high tumor burden state on a per cell basis, reflecting their less exhausted immune status. This elevated IFN-γ secretion in the LTB state therefore contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade. Our report underscores the importance of achieving the optimal magnitude of immune stimulation for successful immunotherapy strategies.

2018-10-24 | GSE121694 | GEO

Autophagy is essential for tumor development and survival in hypoxia and in vivo in glioblastoma. (Provisional)

Project description:Hypoxia is negatively associated with glioblastoma patient survival and contributes strongly to tumor resistance. Unfortunately novel anti-angiogenic therapy increases hypoxia and activates survival pathways in tumor cells leading to inevitable tumor relapse. Here we demonstrate that primary glioma cultures and cell lines depend on autophagy to survive severe hypoxia but also at normal oxygen levels. Positive regulators of autophagy are expressed at higher levels in tumor cells and induction in severe hypoxia is more prominent compared to normal brain cells. We demonstrate that autophagy is an essential/critical target for novel treatment in glioblastoma. We show ATG9A is induced by severe hypoxia and could be a novel player of the autophagic response in glioma cells. ATG9A targeting inhibited tumor growth, suggesting an essential role in glioma cell survival in vivo. While autophagy induction was also observed in normal astrocytes, glioma cells displayed a higher sensitivity towards autophagy inhibitors. Importantly, patient-derived cultures exhibited varying sensitivity towards anti-autophagy treatment, where certain cultures were dependent on autophagy already in normoxic conditions. The treatment of tumor bearing mice with the autophagy inhibitor chloroquine significantly increased mice survival, but combination treatment of the agent with bevacizumab did not reveal additive or synergistic effect. The present study demonstrates that inhibition of autophagy using chloroquine as a single agent provides a novel treatment strategy against glioblastoma. It remains to be seen whether autophagy inhibition will improve current standard of care treatment of newly diagnosed glioblastoma patients and whether more specific inhibitors will lead to stronger therapeutic outcome. (Provisional)

2015-11-10 | E-MTAB-3085 | biostudies-arrayexpress

Resolving the Difference Between Left-sided and Right-sided Colorectal Cancer by Single-cell Sequencing

Project description:Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells, from three left-sided and three right-sided CRC patients were profiled by scRNA-seq. Right-sided CRC harbors a significant proportion of exhausted CD8 T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of “pre-exhausted” to exhausted T cells were favorable prognostic markers. Notably, we identified a novel RBP4+ NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.

2021-11-15 | GSE188711 | GEO

F. nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer

Project description:At present, the mechanisms underlying the association between gut microbiota metabolites and immunotherapy in CRC remain unknown. Here, we conducted a multiomics analysis of a cohort of patients with mCRC and found that F.nucleatum was more abundant in patients who did not respond to immunotherapy. We also found that F. nucleatum diminished the sensitivity to anti-PD-1 mAb through its metabolite succinic acid. Accordingly, patients with lower serum succinic acid levels achieved a better response to immunotherapy. Mechanistically, F.nucleatum-derived succinic acid suppressed the cGAS-interferon-β pathway, consequently dampening the antitumor response by limiting CD8+ T-cell trafficking to the tumor microenvironment in vivo. Treatment with metronidazole reduced intestinal F.nucleatum abundance and thereby decreased serum succinic acid levels, thus resensitizing the tumors to immunotherapy in vivo. Collectively, our findings indicate that F. nucleatum and its metabolite succinic acid induce tumor resistance to immunotherapy and offer new insights into microbiota-metabolite-immune crosstalk in CRC.

2023-12-01 | GSE209864 | GEO

F. nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer

2023-10-01 | GSE181337 | GEO

PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [ATAC-Seq]

Project description:The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCl/i inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCl/i directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCl/i results in increased levels of enzymatically active ULK2 that by direct phosphorylation activates TBK1 to foster the activation of the STING-mediated IFN response. PKCl/i inactivation also triggers autophagy that prevents STING degradation by chaperone-mediated autophagy. Thus, PKCl/i is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single cell multiplex imaging and bioinformatics analysis demonstrated that low PKCl/i levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

2021-09-23 | GSE180223 | GEO

PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [RNA-Seq]

2021-09-23 | GSE180222 | GEO

A tumor suppressive-molecular axis EP300/circRERE/miR-6837-3p/MAVS activates type I interferon pathway and anti-tumor immunity to suppress colorectal cancer

Project description:Purpose: The oncogenic role of circRNAs has been well-studied in cancers including colorectal cancer (CRC). However, tumor-suppressive circRNAs and the mechanism through which they exert their anti-tumor effects remain largely unknown. We aim to find out the critical tumor-suppressive circRNAs and their possibility to serve as gene therapy targets. Experimental Design: CircRNA sequencing, gain- and loss- of function experiments，and transcriptomic analysis were performed to find tumor-suppressive and anti-tumor immunity effects of circRERE. Molecular biology experiments were conducted for mechanism exploration. Finally, we conducted adeno-associated virus to deliver circRERE (circRERE-AAV) and evaluated circRERE-AAV alone and in combination with anti-PD-1 antibody in C57BL/6J mice bearing subcutaneous MC38 tumors. Results: CircRERE is lowly expressed in CRC and its lower expression predicts worse prognosis of CRC patients in clinic. Overexpression of circRERE inhibits the malignant behaviors of CRC in vitro and in vivo, while knockdown exhibits the opposite effects. The expression of circRERE is regulated by EP300, a histone acetyltransferase downregulated in CRC as well. Mechanistically, circRERE acts as a ceRNA to sponge miR-6837-3p to upregulate MAVS expression, thereby activating type I IFN signaling and promoting anti-tumor immunity. Delivery of circRERE-AAV elicits significant anti-tumor effects, and combination treatment with circRERE-AAV and anti-PD-1 antibody exhibits synergistic effects on tumor growth in preclinical models of CRC. Conclusions: These results uncover modulatory axis constituting of EP300/circRERE/miR-6837-3p/MAVS and its essential roles in anti-tumor immunity, and demonstrate that circRERE-AAV might represent a new therapeutic avenue to prime immune responses and boost the effects of immunotherapy in clinic.

2023-03-17 | GSE224734 | GEO

Iron boosts anti-tumor type 1 T-cell responses and anti-PD1 immunotherapy

Project description:Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFN-γ. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 may increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. Such a phenomenon could be the consequence of a metabolic reprogramming of T cells by iron. The "adjuvant" effect of iron results in a strong slowdown of tumor-cell growth after tumor-cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes anti-tumor responses by increasing IFN-γ production by T cells. In addition, iron supplementation considerably improves the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in cancer patients, the quality and efficacy of the anti-tumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of anti-tumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation.

2024-04-02 | GSE262545 | GEO

Bexmarilimab activates human tumor-associated macrophages to support adaptive immune responses in interferon-poor immune microenvironments

Project description:Immune checkpoint inhibitors (ICI) show substantially greater efficacy in inflamed tumors characterized by preexisting T-cell infiltration and IFN signaling than in noninflamed “cold” tumors, which often remain immunotherapy resistant. The cancer immunotherapy bexmarilimab, which inhibits the scavenger receptor Clever-1 to release macrophage immunosuppression and activate adaptive immunity, has shown treatment benefit in subsets of patients with advanced solid malignancies. However, the mechanisms that determine bexmarilimab therapy outcome in individual patients are unknown. Here we characterized bexmarilimab response in ovarian cancer ascites macrophages ex vivo using single-cell RNA-sequencing and demonstrated increased IFN signaling and CXCL10 secretion following bexmarilimab treatment. We further showed that bexmarilimab was most efficacious in macrophages with low baseline IFN signaling, as chronic IFNγ priming abolished bexmarilimab-induced TNFα release. These results highlight an approach to target immunologically cold tumors and to increase the likelihood of their subsequent response to ICIs.

2023-10-30 | GSE222649 | GEO

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