A Protein Kinase D Inhibitor Suppresses AKT on T cells and Antagonizes Cancer Immunotherapy by Anti-PD-1

Antibodies that block interaction between PD-1 and PD-1 ligands (anti-PD-1) are in clinical use for treatment of cancer, yet the efficacy of which is limited. Pre-approved therapies that enhance the effect of anti-PD-1 in combination are beneficial. Small molecule inhibitors that attenuate T cell receptor signaling are reported to prevent T cell exhaustion, induce memory T cells with stem cell potential, resulting in durable effector T cell response in combination with anti-PD-1. In search of such targets, we focused on protein kinase D (PKD) which is suggested to be suppressive in both tumor growth and TCR signaling. We report that CRT0066101, a PKD inhibitor (PKDi) suppressed growth of mouse tumor at sub-micromolar concentration in vitro. Despite its inhibitory effects on tumors, a single treatment of tumor bearing mice with PKDi did not inhibit, but rather accelerated tumor growth, and reversed the therapeutic effect of anti-PD-1. Mice treated with PKDi showed reduced T cell infiltration and defects in generation of effector T cells, compared to that treated with anti-PD-1, suggesting that PKDi inhibited ongoing antitumor responses. Mechanistically, PKDi inhibited phosphorylation of AKT, a primary checkpoint that is reactivated by anti-PD-1. In conclusion, PKD is fundamentally required for T-cell reactivation by anti-PD-1, therefore inhibition of PKD is not appropriate for combination therapy with anti-PD-1. On the other hand, a single dose of PKDi was shown to strongly suppress experimental autoimmunity in mice, indicating that PKDi could be useful for treatment of immune related adverse events, that are frequently reported in anti-PD-1 therapy.

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PKD