A protein kinase D inhibitor suppresses AKT on T cells and antagonizes cancer immunotherapy by anti-PD-1

Kazuhide Miyamoto, Hodaka Hayabuchi, Yukiko Tokifuji, Makoto Ando, Nobuyuki Onishi, Tadashi Okamura, Akihiko Yoshimura, Shunsuke Chikuma

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Antibodies that block the interaction between PD-1 and PD-1 ligands (anti-PD-1) are in clinical use for the treatment of cancer, yet their efficacy 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 and induce memory T cells with stem cell potential, resulting in a 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 the growth of mouse tumors at a 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 the generation of effector T cells, compared to those 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 the treatment of immune-related adverse events that are frequently reported in anti-PD-1 therapy.

Original languageEnglish
Pages (from-to)609-619
Number of pages11
JournalInternational immunology
Volume34
Issue number12
DOIs
Publication statusPublished - 2022 Dec 1

Keywords

  • PD-1
  • T-lymphocytes
  • cancer immunotherapy
  • immune-checkpoint
  • protein kinase D

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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