Revealing profile of cancer-educated platelets and their factors to foster immunotherapy development

Abstract

Among multiple hemostasis components, platelets hyperactivity plays major roles in cancer progression by providing surface and internal components for intercellular crosstalk as well as by behaving like immune cells. Since platelets participate and regulate immunity in homeostatic and disease states, we assumed that revealing platelets profile might help in conceiving novel anti-cancer immune-based strategies. The goal of this review is to compile and discuss the most recent reports on the nature of cancer-associated platelets and their interference with immunotherapy. An increasing number of studies have emphasized active communication between cancer cells and platelets, with platelets promoting cancer cell survival, growth, and metastasis. The anti-cancer potential of platelet-directed therapy has been intensively investigated, and anti-platelet agents may prevent cancer progression and improve the survival of cancer patients. Platelets can (i) reduce antitumor activity; (ii) support immunoregulatory cells and factors generation; (iii) underpin metastasis and, (iv) interfere with immunotherapy by expressing ligands of immune checkpoint receptors. Mediators produced by tumor cell-induced platelet activation support vein thrombosis, constrain anti-tumor T- and natural killer cell response, while contributing to extravasation of tumor cells, metastatic potential, and neovascularization within the tumor. Recent studies showed that attenuation of immunothrombosis, modulation of platelets and their factors have a good perspective in immunotherapy optimization. Particularly, blockade of intra-tumoral platelet-associated programmed death-ligand 1 might promote anti-tumor T cell-induced cytotoxicity. Collectively, these findings suggest that platelets might represent the source of relevant cancer staging biomarkers, as well as promising targets and carriers in immunotherapeutic approaches for combating cancer.

Keywords: Cancer; Immunotherapy; Inflammation; Platelets; Thrombosis.

Graphical abstract

Fig. 1

Normal thrombopoiesis and platelet generation in cancer. Hematopoietic stem cell (HSC) niche MKs in bone marrow and platelet generating MKs in blood. Platelets are generated in the thrombopoiesis by the large, polyploid, and HSC-derived MKs. Paraneoplastic thrombocytosis occurs in many solid tumors.

Fig. 2

Immune context of TCIPA. In an early step of TCIPA, cancer cells trigger platelet granule and extracellular vesicle release to facilitate cancer cell survival in circulation. In turns, platelet profile is reprogrammed toward cancer-educated platelet. Platelet microparticles (PMPs) are produced upon activation in the blood of cancer patients. TCIPA is followed by the attenuated anti-tumor immunity via inhibition of T lymphocytes and NK cells, and macrophage polarization towards M2 tumor-associated macrophages (TAMs). TGF-β derived by platelets reduces natural killer group 2D (NKG2D) receptor expression and inhibits their antitumor reactivity. CXCL4 produced by CEPs induces myeloid derived suppressor cells (MDSCs) generation. Platelet-induced MSC trans-differentiation into CAF-like cells through TGF-β production.