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

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

PROVIDER: PRJNA684574 | ENA |

REPOSITORIES: ENA

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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

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.

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Project description:The goal was to determine the impact of CD155 signaling through CD226 and TIGIT on Tfh differentiation and function based on gene expression.

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

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