Enhancing Anti-Cancer Immunotherapy by Disruption of the non-Receptor Tyrosine Kinase Fes

Cancer immunotherapies are based on the principle that a patient’s own immune system can be engaged to fight their disease. While effective activation of the immune system is crucial for the success of cancer immunotherapies, native checkpoint mechanisms exist to limit immune activation and maintain homeostasis. In the setting of cancer, these checkpoints act as barriers to anti-cancer immunity, and therefore represent important targets for cancer immunotherapy. Here, we demonstrate a novel role of the Fes tyrosine kinase, which is abundantly expressed in macrophages, dendritic cells, NK cells and B cells, as an innate intracellular immune checkpoint. In syngeneic engraftment models of breast cancer and melanoma, FES genetic disruption in the host was associated with delayed tumour growth, improved survival, enhanced response to therapy with doxorubicin, and sensitization of tumours to anti-PD-1 immune checkpoint blockade. These effects were associated with enhanced in vivo ratios of M1/M2 tumour associated macrophages, as well as activation of and PD-1 expression on tumour associated T cells. In vitro, Fes-deficient bone marrow derived macrophages demonstrated an increase in Toll-like receptor signaling in antigen presenting cells, which was associated with an increase in proinflammatory cytokine production and T cell activation capabilities. Furthermore, we demonstrate a novel role for Fes in regulating the retention of cytokines on antigen presenting cell surfaces that may elicit greater downstream signaling in T cells. Our results highlight Fes as a novel innate immune checkpoint with potential as a predictive biomarker for effective immune checkpoint blockade treatment, and a potential therapeutic target to improve this form of anti-cancer immunotherapy.

Department dc:contributor.department

Pathology and Molecular Medicine

Year dc:date.issued

2024

Author dc:creator

• Laight, Brian

Advisor dc:contributor.supervisor

• Greer, Peter

• Cancer
• Cancer Immunotherapy
• Immune Checkpoint
• Innate Immunity
• Macrophage
• Signal 3

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1974/33352

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/33352