Suppression of Natural Killer cell NKG2D and CD226 anti-tumour cascades by platelet cloaked cancer cells: Implications for the metastatic cascade

Abstract

Tumour cell immune evasion is a principal hallmark of successful metastasis. Tumour cells in the vasculature adopt a platelet cloak that efficiently suppresses the innate immune system by directly inhibiting Natural Killer (NK) cells, which normally function to neutralise spreading cancers. Here we describe two novel mechanisms of tumour cell evasion of NK cell anti-tumour functions. The first, an ‘immune decoy’ mechanism in which platelets induce the release of soluble NKG2D ligands from the tumour cell to mask detection and actively suppress NK cell degranulation and inflammatory cytokine (IFNγ) production, concomitantly. This represents a double-hit to immune clearance of malignant cells during metastasis. The second mechanism, a platelet-derived TGFβ-mediated suppression of the CD226/CD96-CD112/CD155 axis, is a novel pathway with poorly understood anti-cancer functions. We have demonstrated that platelets robustly suppress surface expression of CD226 and CD96 on the NK cell surface and their associated ligands on the tumour cell to further enhance NK cell suppression. These highly evolved mechanisms promote successful tumour immune evasion during metastasis and provide a unique opportunity for studying the complexity of cellular interactions in the metastatic cascade and thus novel targets for cancer immunotherapy.

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

“…Assessment of degranulation responses with the GM NK-92 cell-based screening platform showed that NKG2D + GM NK-92 cells had enhanced degranulation against majority of the cell lines except for SH-SY5Y ( Figure 7A). In line with this observation, previous studies and the human protein atlas database demonstrated moderate/high expression of at least one NKG2D ligand in all cell lines used except in the neuroblastoma cell line SH-SY5Y (35)(36)(37)(38)(39)(40)(41). Importantly, identification of differential receptor-mediated responses against tested cells lines such as DM6, THP-1, and ARH-77 cell lines, validates the functionality of each receptor introduced to NK-92 cells, and further demonstrates the applicability of the NK cell-based screening platform for the identification of tumor type-and most importantly patient-specific targetable NK cell receptor/ligand interactions (Figure 7A).…”

Modulation of Immune Responses by Platelet-Derived ADAM10

“…This was mirrored by enhanced detection of soluble NKG2DL, pointing to increased shedding of the surface expressed ligands. These observations were also confirmed by another group evaluating different tumor entities (121). Alike Cluxton and coworkers, we did not find enhanced mRNAlevels of tumor-ADAM10 (or ADAM17) upon platelet coating.…”

Platelets in aging and cancer—“double-edged sword”

“…Additionally, coating of tumor cells with platelets allows transferring their major histocompatibility complex (MHC) class I to tumor cells, thereby giving these cells a false "pseudonormal" exterior, and allowing escape from immunosurveillence by natural killer cells [149]. TGFβ released by platelets also downregulates the NK receptor NKG2D on tumor cells, further shielding them from immunosurveillence [150,151]. Lastly, extravasation of the tumor cells from the blood stream is facilitated by platelets, and appears to require binding of platelets to Integrin ανβ3 expressed on tumor cells [152].…”