TAM Receptor Inhibition–Implications for Cancer and the Immune System

SIMPLE SUMMARY: TAM receptors are a family of receptor tyrosine kinases, comprising Tyro3, Axl and MerTK. Their primary role is in digestion of dying cells by macrophages without alarming the immune system. TAM receptors are also expressed by cancer cells in which signaling is oncogenic, and for this reason there is growing interest and research into TAM inhibition. This approach to cancer treatment may, however, come into conflict with beneficial and costimulatory TAM receptor signaling in T cells and natural killer (NK) cells. The aim of this review is to explore in detail the effects of TAM receptor inhibition on cancer cells and immune cells, and how the ramifications of this inhibition may affect cancer treatment in humans. ABSTRACT: Tyro3, Axl and MerTK (TAM) receptors are receptor tyrosine kinases which play important roles in efferocytosis and in the balancing of immune responses and inflammation. TAM receptor activation is induced upon binding of the ligands protein S (Pros1) or growth arrest-specific protein 6 (Gas6) which act as bridging molecules for binding of phosphatidyl serine (PtdSer) exposed on apoptotic cell membranes. Upon clearance of apoptotic cell material, TAM receptor activation on innate cells suppresses proinflammatory functions, thereby ensuring the immunologically silent removal of apoptotic material in the absence of deleterious immune responses. However, in T cells, MerTK signaling is costimulatory and promotes activation and functional output of the cell. MerTK and Axl are also aberrantly expressed in a range of both hematological and solid tumor malignancies, including breast, lung, melanoma and acute myeloid leukemia, where they have a role in oncogenic signaling. Consequently, TAM receptors are being investigated as therapeutic targets using small molecule inhibitors and have already demonstrated efficacy in mouse tumor models. Thus, inhibition of TAM signaling in cancer cells could have therapeutic value but given the opposing roles of TAM signaling in innate cells and T cells, TAM inhibition could also jeopardize anticancer immune responses. This conflict is discussed in this review, describing the effects of TAM inhibition on cancer cells as well as immune cells, while also examining the intricate interplay of cancer and immune cells in the tumor microenvironment.