The TAM family receptor tyrosine kinases Tyro3, Axl, and Mer are essential regulators of immune homeostasis [9] facilitating the resolution of inflammation [8]. Blocking TAM signaling causes widespread inflammation, and hyper-activation of the immune system and can lead to systemic autoimmunity [6]. In addition, these receptors and their major ligands (growth arrest specific factor 6 (Gas6- a pan-TAM agonist) and protein S (Pros1- activates Tyro3 and Mer)) contribute to several oncogenic processes [5]. The AXL/GAS6 signalling pathway plays a leading role in driving cancer metastasis and acquired drug resistance. Lung, breast, ovarian, kidney and pancreatic cancers, and acute and chronic myeloid leukemias exhibit up-regulated AXL/GAS6 signalling. An elevated GAS6 level correlates with poor prognosis in cancers, and is associated with other diseases both non-inflammatory, and inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus. Tubby, tubby-like protein 1 (Tulp-1) [4], and Galectin-3 [3] have been reported as TAM ligands potentially involved in modulation of phagocytic activity, but their physiological relevance is still unclear. Warfarin is used as a TAM antagonist in research, as it inhibits the γ-carboxylation of TAM ligands necessary for receptor activation. TAM receptors and ligands are predominantly expressed by myeloid cells, including macrophages, dendritic cells, monocytes, platelets, and also by NK and NK T cells. Of particular interest is the identification of the TAM receptor tyrosine kinases (TYRO3, AXL, and MERTK as innate immune checkpoints that could be pharmacologically exploited to promote anti-tumoural immunity [1] (notably these are all inhibited by the multikinase inhibitor and clinical candidate merestinib). TAM inhibition is predicted to activate strong anti-tumour responses. Development of small molecule pharmacological inhibitors of TAM signaling for oncology indications is reviewed in [2]. Therapeutic monoclonal antibodies and antibody-drug conjugates targeting AXL or GAS6 are in development, e.g. Genmab's Phase 1/2 anti-AXL ADC HuMAX-AXL-ADC (NCT02988817) and Amgen's preclinical anti-GAS6 MAbs GMAB1 and GMAB2 [7].

1. Akalu YT, Rothlin CV, Ghosh S. (2017) TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev, 276 (1): 165-177. [PMID:28258690]

2. Baladi T, Abet V, Piguel S. (2015) State-of-the-art of small molecule inhibitors of the TAM family: the point of view of the chemist. Eur J Med Chem, 105: 220-37. [PMID:26498569]

3. Caberoy NB, Alvarado G, Bigcas JL, Li W. (2012) Galectin-3 is a new MerTK-specific eat-me signal. J Cell Physiol, 227 (2): 401-7. [PMID:21792939]

4. Caberoy NB, Zhou Y, Li W. (2010) Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis. EMBO J, 29 (23): 3898-910. [PMID:20978472]

5. Davra V, Kimani SG, Calianese D, Birge RB. (2016) Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response. Cancers (Basel), 8 (12). [PMID:27916840]

6. Lu Q, Lemke G. (2001) Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science, 293 (5528): 306-11. [PMID:11452127]

7. Moody G, Belmontes B, Masterman S, Wang W, King C, Murawsky C, Tsuruda T, Liu S, Radinsky R, Beltran PJ. (2016) Antibody-mediated neutralization of autocrine Gas6 inhibits the growth of pancreatic ductal adenocarcinoma tumors in vivo. Int J Cancer, 139 (6): 1340-9. [PMID:27170265]

8. Paolino M, Penninger JM. (2016) The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy. Cancers (Basel), 8 (10). [PMID:27775650]

9. Rothlin CV, Carrera-Silva EA, Bosurgi L, Ghosh S. (2015) TAM receptor signaling in immune homeostasis. Annu Rev Immunol, 33: 355-91. [PMID:25594431]