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Genome-wide screens identify FBOX11-CCNC axis as a suppressor of CD155 mediated cancer immune evasion

ABSTRACT: Genome-wide screens identify FBOX11-CCNC axis as a suppressor of CD155 mediated cancer immune evasion

PROVIDER: PRJNA1169545 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30895717_1.fastq.gz	Fastqsanger.gz
	SRR30895717_2.fastq.gz	Fastqsanger.gz
	SRR30895718_1.fastq.gz	Fastqsanger.gz
	SRR30895718_2.fastq.gz	Fastqsanger.gz
	SRR30895719_1.fastq.gz	Fastqsanger.gz

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Genome-wide screens identify FBOX11-CCNC axis as a suppressor of CD155 mediated cancer immune evasion

Project description:The CD155/TIGIT axis plays a crucial role in the suppression of anti-tumor responses. The clinical benefit for patients with diverse types of advanced cancers that has been observed upon blockade of the interaction between CD155 and TIGIT has highlighted the need to study the mechanisms by which CD155 is regulated. Here we identify Cyclin C (CCNC) as a novel modulator of CD155 by using a genome-wide CRISPR-Cas9 screen. Notably, CCNC depletion increases the CD155 expression at the transcriptional level in a broad range of cancer cells. We further found that CCNC suppresses the CD155 expression by inhibiting the transcriptional activity of FOSL2. We further found that the stability of CCNC is negatively regulated by the E3 ubiquitin ligase complex component FBXO11. Functionally, CCNC depletion significantly suppresses the anti-tumor activity of natural killer (NK) and T cells both in vitro and in vivo. Clinically, the expression level of CCNC is negatively correlated with CD155 in cancer patient tissues. Together, our findings provide insights into the biology of CD155 regulation, identify a previously unrecognized master regulator of this critical immune checkpoint and highlight a combination immunotherapy (TIGIT/PD-1 co-blockade) as a promising anti-cancer therapeutic strategy to overcome immune evasion by CCNC-deficient tumor cells.

2024-10-11 | GSE278902 | GEO

The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

Project description:The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using two novel preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, which are similar to tumor-infiltrating lymphocytes of human PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical to maintain immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.

2021-07-25 | GSE163059 | GEO

The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

Project description:The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

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Plasticity of ether lipids promotes ferroptosis susceptibility and evasion

Project description:Ferroptosis, an iron-dependent, non-apoptotic cell death program, is involved in a variety of degenerative diseases and represents a targetable vulnerability in certain cancers. The ferroptosis-susceptible cell-state can either preexist in cells arising from certain lineages or be acquired during cell-state transitions. Precisely how ferroptosis susceptibility is dynamically regulated remains poorly understood. Using genome-wide CRISPR/Cas9 suppressor screens, we identify a key role for peroxisome–ether phospholipid genes in driving ferroptosis susceptibility and evasion in ovarian cancer.

2020-09-16 | GSE151062 | GEO

High-resolution CRISPR/Cas9 screens identify PAK2 as a suppressor of macrophage proliferation and macropinocytosis.

Project description:High-resolution CRISPR/Cas9 screens identify PAK2 as a suppressor of macrophage proliferation and macropinocytosis.

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In vivo CRISPR screens identify Mga as an immunotherapy target in triple-negative breast cancer

Project description:Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. We also provided a high-confidence valuable dataset for the understanding of tumor intrinsic immunomodulators and the discovery of novel anti-cancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances anti-tumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga functions through, at least partially, repression of MHC-II genes and related immune responses. Consistently, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-g signaling. Our findings provide new insights into tumor immune escape and pave the way for further exploration of MGA inhibition for clinical benefits in triple-negative breast cancer.

2024-09-06 | GSE249759 | GEO

Tumor FAK Orchestrates Immunosuppression in Ovarian Cancer via the CD155/TIGIT axis

Project description:Tumor FAK Orchestrates Immunosuppression in Ovarian Cancer via the CD155/TIGIT axis

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Project description:All bulk CRISPR based screens CD2 and B2M CRISPRi tiling screens (primary human CD8 T cells), IL2RA CRISPRa tiling screens (Jurkats), CRISPRi/a TF screens (primary human CD8 T cells), and CRISPR TFome KO (primary human T cells)

2023-08-31 | GSE241933 | GEO

T cells produce interleukin-22 to promote CD155-driven lung metastasis

Project description:T cells are key players in immunosurveillance and anti-tumor immunity. However, subsets of T helper cells producing high levels of interleukin-22 (IL-22) accumulate in primary breast and lung tumors and are linked to a more dismal outcome. Here, we demonstrate that such TH22 cells promote metastasis by abrogating NK cell-mediated immune surveillance. Using mouse models of metastatic lung and breast cancer, we find that secreted IL-22 acts directly on disseminated cancer cells expressing the IL-22 receptor (IL-22R). In turn, IL-22 induces cancer cell overexpression of CD155, which binds to activating receptor CD226 on the surface of NK cells and triggers its downregulation. This functionally impairs NK cells to promote lung metastases. Importantly, neutralization of IL-22 in vivo blocked the metastatic potential of cancer cells, suggestive of therapeutic exploitability. We confirmed the paramount role of IL-22 signaling that was associated with CD155 expression in human datasets and marked poor patient outcomes. This study reveals an immunosuppressive feedback loop activated by T cell-derived IL-22 in cancer progression, creating the rationale for the development of future targeted therapeutics.

2022-06-30 | GSE202314 | GEO

Functional genomic landscape of cancer-intrinsic immune evasion to cytotoxic T lymphocyte killing [CRISPRseq]

Project description:The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood. To identify a phenotypically robust core set of genes and pathways that facilitate cancer cell-intrinsic evasion to cytotoxic T lymphocyte (CTL)-mediated killing, we performed genome-wide CRISPR screens across a panel of genetically diverse cancer models cultured in the presence of CTLs. We uncovered a core set of 182 genes whose individual perturbation leads to either cancer cell sensitivity or resistance to CTL toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated nature by which genes and pathways act to orchestrate intrinsic CTL evasion, with discrete functional modules controlling the interferon response and tumor necrosis factor alpha (TNFa)-induced cytotoxicity emerging as dominant sub-phenotypes. Our data establish a central role for previously identified negative regulators of the Type II interferon response (e.g. Ptpn2, Socs1, Adar1) in mediating intrinsic CTL evasion and demonstrate a requirement for the lipid droplet related gene Fitm2 for maintaining cell fitness upon exposure to interferon gamma (IFNg). Additionally, we identify the autophagy pathway as a conserved mediator of cancer intrinsic CTL evasion, required to resist cytokine-mediated cytotoxicity caused by IFNg and TNFa. By mapping cytokine- and CTL-based genetic interactions, as well as in vivo CRISPR screens, we illuminate the pleiotropic nature by which autophagy acts to orchestrate intrinsic CTL evasion and highlight the importance of our observed effects within the tumor microenvironment. Collectively, our data expands our appreciation of the genetic circuits that contribute to cancer intrinsic immune evasion, highlighting the importance of leveraging systematic functional genomics approaches for furthering our understanding of this biology.

2020-07-31 | GSE153397 | GEO

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