Platelet-Derived Transforming Growth Factor-β Down-Regulates NKG2D Thereby Inhibiting Natural Killer Cell Antitumor Reactivity
2009/09/09 by Hans-Georg Kopp, Hans‐Georg Kopp, Theresa Placke +2 · 28 citations
Immunology and Microbiology · #Immune Cell Function and Interaction #T-cell and B-cell Immunology #Immune cells in cancer
paper · doi:10.1158/0008-5472.can-09-2123
Abstract
Natural killer (NK) cells play an important role in cancer immunosurveillance and may prevent tumor progression and metastasis due to their ability to mediate direct cellular cytotoxicity and by releasing immunoregulatory cytokines, which shape adaptive immune responses. Their reactivity is governed by various activating and inhibitory molecules expressed on target cells and reciprocal interactions with other hematopoietic cells such as dendritic cells. In mice, thrombocytopenia inhibits metastasis, and this is reversed by NK cell depletion, suggesting that platelets are an important additional player in NK cell-tumor interaction. Moreover, it has been shown that metastasizing tumor cells do not travel through the blood alone but are rapidly coated by platelets. However, the knowledge about the molecular mechanisms by which platelets influence NK cells is fragmentary at best. Here we show that platelet-derived soluble factors, secreted on coating of tumor cells or after stimulation with classic platelet agonists, impair NK cell antitumor reactivity resulting in diminished granule mobilization, cytotoxicity, and IFN-gamma production. The impaired NK cell reactivity was not due to induction of apoptosis but mediated by down-regulation of the activating immunoreceptor natural killer group 2, member D (NKG2D) on NK cells by platelet-derived transforming growth factor beta (TGF-beta). Neutralization of TGF-beta in platelet releasate not only prevented NKG2D down-regulation but also restored NK cell antitumor reactivity. Thus, our data elucidate the molecular basis of the previously described influence of platelets on NK cell antitumor reactivity and suggest that therapeutic intervention in tumor cell-platelet interaction and the resulting TGF-beta release by platelets may serve to enhance antitumor immunity.
Cited by
- Preoperative platelet to lymphocyte ratio predicts outcome of patients with pancreatic ductal adenocarcinoma after pancreatic resection
- Surgery-mediated tumor-promoting effects on the immune microenvironment
- Innate immune receptors in platelets and platelet-leukocyte interactions
- Effect of NKG2D ligand expression on host immune responses. [europepmc]
- TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. [europepmc]
- The polarization of immune cells in the tumour environment by TGFbeta. [europepmc]
- Transforming growth factor-β and the hallmarks of cancer. [europepmc]
- Contribution of platelets to tumour metastasis. [europepmc]
- The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. [europepmc]
- Platelets, coagulation and fibrinolysis in breast cancer progression. [europepmc]
- Emerging Biological Principles of Metastasis. [europepmc]
- Platelets subvert T cell immunity against cancer via GARP-TGFβ axis. [europepmc]
- Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis. [europepmc]
- The Platelet Lifeline to Cancer: Challenges and Opportunities. [europepmc]
- Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade. [europepmc]
- Role of platelets and platelet receptors in cancer metastasis. [europepmc]
- Overcoming Resistance to Natural Killer Cell Based Immunotherapies for Solid Tumors. [europepmc]
- Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities. [europepmc]
- Impairment of NKG2D-Mediated Tumor Immunity by TGF-β. [europepmc]
- Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β. [europepmc]
- Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors. [europepmc]
- The Immune Nature of Platelets Revisited. [europepmc]
- Heparanase and the hallmarks of cancer. [europepmc]
- Platelets, immune cells and the coagulation cascade; friend or foe of the circulating tumour cell? [europepmc]
- Circulating tumor cells: biology and clinical significance. [europepmc]
- Detection of circulating tumor cells: opportunities and challenges. [europepmc]
- CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. [europepmc]
- Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. [europepmc]
Related