Abstract B02: Targeting CSK kinase activity to enhance antitumor immunity

Abstract

Abstract To mount an effective tumor immune response, a T cell receptor (TCR) must first recognize a cognate antigen presented by the malignant cells. This antigen-TCR engagement at the cell surface initiates an intracellular signaling cascade that leads to the upregulation of pro-inflammatory and cytolytic cytokines. Successful effector T cell activation in turn results 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 knock-out mice was engineered to bypass the embryonic lethality observed with constitutive systemic CSK depletion. As expected loss of CSK enhanced cytokine production and increased anti-tumor 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 anti-tumor 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 further optimization in target coverage and dosing regimen. 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, Ruki Eraslan, Miguel Sanjuan, Gregory Vite, Jack Hunt, Brian Fink, Susan Wee. Targeting CSK kinase activity to enhance antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B02.