The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Abstract

The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

Cabozantinib in Combination with Immunotherapy for Advanced Renal Cell Carcinoma and Urothelial Carcinoma: Rationale and Clinical Evidence

“…Cabozantinib is an inhibitor of multiple receptor tyrosine kinases including VEGFR, MET, the TAM kinases, KIT, FLT3, TRKB, and TIE2 (43). In addition to their roles in angiogenesis, tumor growth, and metastasis, several targets of cabozantinib play a role in immunosuppression, particularly VEGFR, MET, and the TAM kinases (17,(44)(45)(46). Inhibition of these signaling molecules likely contributes to the antitumor immunomodulatory effect of cabozantinib ( Fig.…”

“…This neutrophilmediated suppression was blocked by MET inhibition with a concomitant increase in tumor response to checkpoint inhibition (54). The TAM kinases play an important role in maintaining immune homeostasis and are expressed on innate immune cells such as DCs, macrophages, monocytes, and natural killer cells (45,46). TAM receptor triple-knockout mice develop multiorgan autoimmune disease, reflecting the normal physiologic role of these kinases in limiting immune responses.…”

Tumour-Secreted Protein S (ProS1) Activates a Tyro3-Erk Signalling Axis and Protects Cancer Cells from Apoptosis

“…The TAM (Tyro3, Axl, MerTK) subfamily of transmembrane receptor tyrosine kinases (RTKs) has been shown to regulate normal physiological processes such as tissue homeostasis and innate immunity [1]. Consequently, dysregulation of TAM signalling has been associated with chronic inflammatory and autoimmune conditions [2][3][4]. In addition, TAM signalling has been implicated in cancers, where each TAM RTK has in different studies been shown to regulate cancer cell growth, survival, proliferation, differentiation, migration or invasion [1,5].…”

Mechanism of Mer receptor tyrosine kinase inhibition of glomerular endothelial cell inflammation

“…TAM ( T yro-3, A xl, and M er) receptor tyrosine kinases are essential regulators of immune homeostasis that dampen the activation of immune cells and restore tissue function by promoting tissue repair and clearance of apoptotic cells [6–8]. TAM-dependent pathways act as a negative feedback mechanism that suppresses inflammation [7].…”