Enhancing Anti-Cancer Immunotherapy by Disruption of the non-Receptor Tyrosine Kinase Fes
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Authors
Laight, Brian
Date
2024-09-05
Type
thesis
Language
eng
Keyword
Cancer , Cancer Immunotherapy , Immune Checkpoint , Innate Immunity , Macrophage , Signal 3
Alternative Title
Abstract
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.
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Attribution-NonCommercial-NoDerivatives 4.0 International
Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.