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Published on: January 22, 2019
CD317 mediates immunocytolysis resistance by RICH2/cytoskeleton-dependent membrane protection
Jian Cheng1, Zhao Liu2, Tian Deng2
1Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China.
Abstract:
Immune evasion is a common hallmark of cancers. Immunotherapies that aim at restoring or increasing the immune response against cancers have revolutionized outcomes for patients, but the mechanisms of resistance remain poorly defined. Here, we report that CD317, a surface molecule with a unique topology that is double anchored into the membrane, protects tumor cells from immunocytolysis. CD317 knockdown in tumor cells renders more severe death in response to NK or chimeric antigen receptor-modified NK cells challenge. Such effects of CD317 silencing might be the results of increasing sensitivity of tumor cells to immune killing rather than strengthening immune response, since neither effector-target cell contact nor the activation of effector cells was affected, and the enhanced cytolysis was also not counteracted by the addition of recombinant CD317 proteins. Mechanistically, CD317 might endow tumor cells with more flexibility to modulate cytoskeleton through its association with RICH2, thereby protects membrane integrity against perforin and consequently promotes survival in response to immunocytolysis. These results reveal a new mechanism of immunocytolysis resistance and suggest CD317 as an attractive target which can be exploited for improving the efficacy of cancer immunotherapies.
Insights
CD317, a cell surface molecule, helps cancer cells evade immune attack. Reducing CD317 increases tumor cell sensitivity to immune killing, offering a new target for cancer immunotherapy.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Cancer immune evasion is a significant challenge in oncology.
- Immunotherapies have improved patient outcomes but face resistance.
- Mechanisms of cancer resistance to immunotherapy are not fully understood.
Purpose of the Study:
- To investigate the role of CD317 in cancer cell resistance to immune attack.
- To elucidate the molecular mechanisms by which CD317 mediates immune evasion.
- To explore CD317 as a potential therapeutic target for enhancing cancer immunotherapy.
Main Methods:
- CD317 knockdown in tumor cells.
- Assessment of tumor cell sensitivity to Natural Killer (NK) cells and chimeric antigen receptor (CAR)-NK cells.
- Analysis of effector-target cell interactions and effector cell activation.
- Investigation of CD317's association with RICH2 and its effect on the cytoskeleton.
Main Results:
- CD317 knockdown significantly increased tumor cell death upon challenge with immune cells.
- The enhanced killing was due to increased tumor cell sensitivity, not altered immune cell function.
- CD317's association with RICH2 appears to protect tumor cell membrane integrity against cytotoxic molecules like perforin.
- CD317 contributes to cancer cell survival during immunocytolysis.
Conclusions:
- CD317 is a novel mediator of cancer cell resistance to immunocytolysis.
- Targeting CD317 may overcome resistance mechanisms in cancer immunotherapy.
- CD317 represents a promising target for improving the efficacy of existing immunotherapies.
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