Over the past decade, immune checkpoint inhibitor (ICI) therapy has been established as the standard of care for many types of cancer, but the strategies employed have continued to evolve. Recently, much clinical focus has been on combining targeted therapies with ICI for the purpose of manipulating the immune setpoint. The latter concept describes the equilibrium between factors that promote and those that suppress anti-cancer immunity. Besides tumor mutational load and other cancer cell-intrinsic determinants, the immune setpoint is also governed by the cells of the tumor microenvironment and how they are coerced by cancer cells to support the survival and growth of the tumor. These regulatory mechanisms provide therapeutic opportunities to intervene and reduce immune suppression via application of small molecule inhibitors and antibody-based therapies against (receptor) tyrosine kinases and thereby improve the response to ICIs. This article reviews how tyrosine kinase signaling in the tumor microenvironment can promote immune suppression and highlights how therapeutic strategies directed against specific tyrosine kinases can be used to lower the immune setpoint and elicit more effective anti-tumor immunity.
Funding
Cancer research in the authors' laboratories is funded by the National Health and Medical Research Council (NHMRC) of Australia, the National Breast Cancer Foundation, Cancer Australia, Cure Brain Cancer Foundation, Australian Cancer Research Foundation, the Cancer Council of Victoria and US Department of Defense. The clinical work of O.K. and A.M.S. is in part supported by the Medical Research Future Fund of Australia and studies supported by Bristol Myers Squibb. M.E. and A.M.S. are Investigators of the NHMRC and additional funding from the Victorian State Government Infrastructure Support program to the authors' institutions is acknowledged.
History
Publication Date
2022-09-29Journal
Molecular CancerVolume
21Article Number
189Pagination
20p.Publisher
Springer NatureISSN
1476-4598Rights Statement
© The Author(s) 2022.
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