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The role of NK cells and CD39 in the immunological control of tumor metastases.

ABSTRACT: Tumor metastases are responsible for death in the majority of cancer patients. Here we have explored the role of the ectonucleotidase CD39 in select models of tumor metastases and further tested the therapeutic anticancer activity of the NTPDase inhibitor sodium polyoxotungstate (POM-1). CD39 was expressed on tumor-infiltrating regulatory T cells (Treg), myeloid cells and some NK cells, and it was upregulated on these cells within tumors early after inoculation in vivo. NK cell numbers and effector functions were increased in globally CD39-deficient mice and also in WT mice treated with POM-1. Dosing with POM-1 suppressed experimental and spontaneous metastases in four different tumor models and was well tolerated. This anti-metastatic activity was completely abrogated in mice, that were depleted of NK cells, had IFNγ neutralized or were deficient in CD39 expression in bone marrow-derived cells. POM-1 was highly effective in suppressing metastases when used in combination with BRAFi/MEKi or anti-PD-1/anti-CTLA-4 or IL-2. These data highlight the importance of the CD39 pathway in suppressing NK cell-mediated anti-tumor immunity and validate further the development of CD39-based therapies in the clinic.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6492967 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The role of NK cells and CD39 in the immunological control of tumor metastases.

Zhang Haiyan H Vijayan Dipti D Li Xian-Yang XY Robson Simon C SC Geetha Nishamol N Teng Michele W L MWL Smyth Mark J MJ

Oncoimmunology 20190402 6

Tumor metastases are responsible for death in the majority of cancer patients. Here we have explored the role of the ectonucleotidase CD39 in select models of tumor metastases and further tested the therapeutic anticancer activity of the NTPDase inhibitor sodium polyoxotungstate (POM-1). CD39 was expressed on tumor-infiltrating regulatory T cells (Treg), myeloid cells and some NK cells, and it was upregulated on these cells within tumors early after inoculation in vivo. NK cell numbers and effec ...[more]

PMID: 31069159

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Project description:BackgroundTumor cells continue to evolve the metastatic potential in response to signals provided by the external microenvironment during metastasis. Platelets closely interact with tumor cells during hematogenous metastasis and facilitate tumor development. However, the molecular mechanisms underlying this process are not fully understood.MethodsRNA-sequencing was performed to screen differentially expressed genes mediated by platelets. The effects of platelet and CD39 on tumor metastasis were determined by experimental metastasis models with WT, NCG and CD39-/- mice.ResultsRNA-sequencing results showed that platelets significantly up-regulated CD39 expression in tumor cells. CD39 is a novel immune checkpoint molecule and a key driver of immunosuppression. Our data provided evidence that the expression of CD39 was enhanced by platelets in a platelet-tumor cell contact dependent manner. Although the role of CD39 expressed by immune cells is well established, the effect of CD39 expressed by tumor cells on tumor cell behavior, anti-tumor immunity and tumor metastasis is unclear. We found that CD39 promoted tumor cell invasion, but had no effect on proliferation and migration. Notably, we showed that the ability of platelets to prime tumor cells for metastasis depends on CD39 in the experimental tumor metastasis model. CD39 silencing resulted in fewer experimental metastasis formation, and this anti-metastasis effect was significantly reduced in platelet-depleted mice. Furthermore, overexpression of CD39 in tumor cells promoted metastasis. In order to eliminate the effect of CD39 expressed in cells other than tumor cells, we detected tumor metastasis in CD39-/- mice and obtained similar results. Moreover, overexpression of CD39 in tumor cells inhibited antitumor immunity. Finally, the data from human samples also supported our findings.ConclusionsOur study shows that direct contact with platelets induces CD39 expression in tumor cells, leading to immune suppression and promotion of metastasis.

Dataset Information

The role of NK cells and CD39 in the immunological control of tumor metastases.

Publications

The role of NK cells and CD39 in the immunological control of tumor metastases.

Similar Datasets

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