Abstract
The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated.
Highlights
Natural killer (NK) cells represent the largest fraction of innate lymphocytes, accounting for 10–15% of all peripheral lymphocytes in humans [1, 2], The physiological importance of NK cells is commonly ascribed to their capability to form early responses against viral infections and malignant cells [3]
It is a common goal to maximize cytotoxicity to achieve tumor eradication. While it remains so far elusive if and to which extent the killing capacity of cellular therapy products are reduced by platelets in the tumor microenvironment, we extrapolate that the infused cellular therapies are likewise inhibited by platelets
Similar considerations apply to further immunotherapies, that rely on tumor cell lysis mediated by other cytotoxic lymphocytes, especially the inhibition of checkpoints for T cell activation e.g., by anti-CTLA4, anti-PD1 or antiPDL1 antibodies, as well as therapies with engineered T cells
Summary
Natural killer (NK) cells represent the largest fraction of innate lymphocytes, accounting for 10–15% of all peripheral lymphocytes in humans [1, 2], The physiological importance of NK cells is commonly ascribed to their capability to form early responses against viral infections and malignant cells [3]. In the context of cancer, they have been shown to support various steps of tumor expansion, including local growth, migration in and out of the blood stream and metastasis establishment During several of those steps platelets are important for evasion of the immune system [20]. A meta-analysis including 1,340 cancer patients that were treated with an immune checkpoint inhibitor, showed a clear advantage of patients with a low PLR [33] These observational studies gave rise to the question if platelet count and PLR are mere surrogate markers indicating strong systemic inflammatory response, reflecting advanced progression, or if clinically relevant interactions between platelets and lymphocytes can influence the disease outcome by themselves. The TGF-β provided by platelets can restrain cellular immune responses in solid tumors, as well as in the bone marrow microenvironment of hematological malignancies and support the survival of cancer cells
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