TAM Family Kinases As Therapeutic Targets at the Interface of Cancer and Immunity

Overview

Journal Nat Rev Clin Oncol

Specialty Oncology

Date 2023 Sep 4

PMID 37667010

Authors

Deborah DeRyckere

Justus M Huelse

H Shelton Earp

Douglas K Graham

Affiliations

Soon will be listed here.

Abstract

Novel treatment approaches are needed to overcome innate and acquired mechanisms of resistance to current anticancer therapies in cancer cells and the tumour immune microenvironment. The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) are potential therapeutic targets in a wide range of cancers. In cancer cells, TAM RTKs activate signalling pathways that promote cell survival, metastasis and resistance to a variety of chemotherapeutic agents and targeted therapies. TAM RTKs also function in innate immune cells, contributing to various mechanisms that suppress antitumour immunity and promote resistance to immune-checkpoint inhibitors. Therefore, TAM antagonists provide an unprecedented opportunity for both direct and immune-mediated therapeutic activity provided by inhibition of a single target, and are likely to be particularly effective when used in combination with other cancer therapies. To exploit this potential, a variety of agents have been designed to selectively target TAM RTKs, many of which have now entered clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians, including an overview of the rationale for therapeutic targeting of TAM RTKs in cancer cells and the tumour immune microenvironment, a description of the current preclinical and clinical experience with TAM inhibitors, and a perspective on strategies for continued development of TAM-targeted agents for oncology applications.

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References

Graham D, DeRyckere D, Davies K, Earp H . The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2015; 14(12):769-85. DOI: 10.1038/nrc3847. View

Lew E, Oh J, Burrola P, Lax I, Zagorska A, Traves P . Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. Elife. 2014; 3. PMC: 4206827. DOI: 10.7554/eLife.03385. View

Behrens E, Gadue P, Gong S, Garrett S, Stein P, Cohen P . The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity. Eur J Immunol. 2003; 33(8):2160-7. DOI: 10.1002/eji.200324076. View

Rothlin C, Carrera-Silva E, Bosurgi L, Ghosh S . TAM receptor signaling in immune homeostasis. Annu Rev Immunol. 2015; 33:355-91. PMC: 4491918. DOI: 10.1146/annurev-immunol-032414-112103. View

Scott R, McMahon E, Pop S, Reap E, Caricchio R, Cohen P . Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature. 2001; 411(6834):207-11. DOI: 10.1038/35075603. View

Seitz H, Camenisch T, Lemke G, Earp H, Matsushima G . Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol. 2007; 178(9):5635-42. DOI: 10.4049/jimmunol.178.9.5635. View

Mao Y, Finnemann S . Regulation of phagocytosis by Rho GTPases. Small GTPases. 2015; 6(2):89-99. PMC: 4601285. DOI: 10.4161/21541248.2014.989785. View

Wu Y, Singh S, Georgescu M, Birge R . A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci. 2005; 118(Pt 3):539-53. DOI: 10.1242/jcs.01632. View

Nishi C, Toda S, Segawa K, Nagata S . Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages. Mol Cell Biol. 2014; 34(8):1512-20. PMC: 3993587. DOI: 10.1128/MCB.01394-13. View

10.

Subramanian M, Hayes C, Thome J, Thorp E, Matsushima G, Herz J . An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J Clin Invest. 2014; 124(3):1296-308. PMC: 3934164. DOI: 10.1172/JCI72051. View

11.

Lu Q, Lemke G . Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science. 2001; 293(5528):306-11. DOI: 10.1126/science.1061663. View

12.

Camenisch T, Koller B, Earp H, Matsushima G . A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J Immunol. 1999; 162(6):3498-503. View

13.

Alciato F, Sainaghi P, Sola D, Castello L, Avanzi G . TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages. J Leukoc Biol. 2010; 87(5):869-75. DOI: 10.1189/jlb.0909610. View

14.

Deng T, Zhang Y, Chen Q, Yan K, Han D . Toll-like receptor-mediated inhibition of Gas6 and ProS expression facilitates inflammatory cytokine production in mouse macrophages. Immunology. 2011; 135(1):40-50. PMC: 3246651. DOI: 10.1111/j.1365-2567.2011.03511.x. View

15.

Zizzo G, Hilliard B, Monestier M, Cohen P . Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol. 2012; 189(7):3508-20. PMC: 3465703. DOI: 10.4049/jimmunol.1200662. View

16.

Ubil E, Caskey L, Holtzhausen A, Hunter D, Story C, Earp H . Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. J Clin Invest. 2018; 128(6):2356-2369. PMC: 5983338. DOI: 10.1172/JCI97354. View

17.

Lin J, Xu A, Jin J, Zhang M, Lou J, Qian C . MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression. Oncoimmunology. 2022; 11(1):2024941. PMC: 8757471. DOI: 10.1080/2162402X.2021.2024941. View

18.

Fujimori T, Grabiec A, Kaur M, Bell T, Fujino N, Cook P . The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung. Mucosal Immunol. 2015; 8(5):1021-1030. PMC: 4430298. DOI: 10.1038/mi.2014.129. View

19.

Sharif M, Sosic D, Rothlin C, Kelly E, Lemke G, Olson E . Twist mediates suppression of inflammation by type I IFNs and Axl. J Exp Med. 2006; 203(8):1891-901. PMC: 2118370. DOI: 10.1084/jem.20051725. View

20.

Yi Z, Li L, Matsushima G, Earp H, Wang B, Tisch R . A novel role for c-Src and STAT3 in apoptotic cell-mediated MerTK-dependent immunoregulation of dendritic cells. Blood. 2009; 114(15):3191-8. PMC: 2759647. DOI: 10.1182/blood-2009-03-207522. View