Abstract

Abstract To mount an effective immune response, a T-cell receptor (TCR) must first recognize a cognate antigen presented by malignant cells. Successful effector T-cell activation initiates an intracellular signaling cascade that results in the release of cytotoxins and proinflammatory cytokines that ultimately result in the elimination of antigen-presenting diseased cells. A key regulator of this signaling cascade is the C-terminal Src (CSK) kinase. In lymphocytes CSK inhibits T-cell activation by phosphorylating the SRC kinase family member LCK at tyrosine 505 and thereby terminates the signaling cascade. To assess whether relieving an intracellular blockade of TCR signaling will lead to a more robust T-cell response, and hence improved tumor immunity, we developed both genetic and pharmacologic approaches to inhibit CSK activity. A tamoxifen-inducible transgenic CSK knockout mouse was engineered to bypass the embryonic lethality observed with constitutive systemic CSK depletion. As expected, loss of CSK enhanced cytokine production and increased antitumor immune response in the MC38 syngeneic tumor mouse model. Potent and selective CSK small-molecule inhibitors, in the presence of TCR stimulation, similarly activated the proximal TCR signaling pathway and increased cytokine production and proliferation. In an in vivo efficacy study, however, the CSK inhibitor as monotherapy or in combination with aPD1 did not improve antitumor immune response at the dose levels tested. This seemingly discrepant finding in tumor response observed in the tamoxifen-inducible KO mice and mice treated with the CSK inhibitor may reflect the need for a more optimized dosing regimen and target coverage. In this poster, we will present our findings on the role of CSK inhibition in tumor immunity. Citation Format: Cindy Wang, Carolyn Cao, Lisa Berman-Booty, Jesse Swanson, Rukiye Eraslan, Miguel Sanjuan, Gregory Vite, Lan-Ying Qin, John Hunt, Brian Fink, Susan Wee. Targeting CSK kinase activity to enhance antitumor immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B198.

Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.