Multiprong CD38 targeting to enhance anti-PD1 immune checkpoint blockade efficacy

Oncoimmunology. 2024 Sep 12;13(1):2400429. doi: 10.1080/2162402X.2024.2400429. eCollection 2024.

Abstract

CD38, a multifunctional enzyme involved in NAD+ catabolism, is hypothesized to act as a metabolic checkpoint for antitumor CD8 T cells. A recent study discovered that, apart from its direct metabolic mechanisms, CD38-mediated RyR2-AKT-TCF1 signaling regulates responsiveness to anti-PD1 cancer therapy at the molecular level. These findings advocate multiprong CD38 targeting to overcome resistance to immune checkpoint blockade therapy.

Keywords: CD38; Cancer immunotherapy; PD1; T cell exhaustion; TCF1; immune checkpoint blockade; metabolism.

MeSH terms

  • ADP-ribosyl Cyclase 1* / antagonists & inhibitors
  • ADP-ribosyl Cyclase 1* / immunology
  • ADP-ribosyl Cyclase 1* / metabolism
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / metabolism
  • Neoplasms* / drug therapy
  • Neoplasms* / immunology
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / immunology
  • Programmed Cell Death 1 Receptor* / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects

Substances

  • ADP-ribosyl Cyclase 1
  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • CD38 protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • HNF1A protein, human
  • Membrane Glycoproteins
  • PDCD1 protein, human
  • Proto-Oncogene Proteins c-akt

Grants and funding

S.G. is supported by grants from the Canadian Institutes of Health Research (CIHR), Canadian Cancer Society (CCS), Canada Foundation for Innovation- John R. Evans Leaders Fund (CFI-JELF), and Research Nova Scotia (RNS). PN is the Linnea Veinotte Scholar trainee in the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, supported by GIVETOLIVE.