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Targeting G Protein-Coupled Receptors in Immuno-Oncological Therapies

John Stagg1, J Silvio Gutkind2

  • 1Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada;

Annual Review of Pharmacology and Toxicology
|September 13, 2024
PubMed

Insights

Cancer immunotherapy using immune checkpoint blockade (ICB) shows promise, but not all patients respond. Targeting G protein-coupled receptors (GPCRs) offers a new strategy to improve treatment effectiveness and achieve lasting remission.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Cancer immunotherapy, particularly immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4, has transformed cancer treatment.
  • A significant number of cancers do not respond to current ICB therapies, necessitating novel therapeutic strategies.
  • G protein-coupled receptors (GPCRs), a major drug target class, remain largely unexplored in cancer immunotherapy.

Purpose of the Study:

  • To review the critical role of GPCRs in regulating immune cell migration and function within the tumor microenvironment.
  • To explore how single-cell transcriptomics reveals the intricate landscape of the human tumor immune GPCRome.
  • To identify new therapeutic opportunities for targeting GPCRs to enhance ICB efficacy in various human cancers.

Main Methods:

  • Literature review focusing on GPCRs in cancer immunology.
  • Analysis of single-cell transcriptomic data to map the tumor immune GPCRome.
  • Discussion of GPCRs expressed on CD8 T cells and their activation by tumor microenvironment factors.

Main Results:

  • GPCRs play a central role in immune cell trafficking and activity.
  • Single-cell transcriptomics provides detailed insights into the GPCR expression patterns in the tumor immune microenvironment.
  • Specific GPCRs on CD8 T cells are activated by tumor-associated mediators, leading to T cell dysfunction.

Conclusions:

  • GPCRs are crucial regulators of immune responses in cancer.
  • Targeting GPCRs presents a promising avenue for overcoming resistance to ICB.
  • A multimodal therapeutic approach involving GPCRs could significantly improve outcomes for diverse human malignancies.
Keywords:
GPCRPD-1T cell exhaustionadenosineimmune checkpointimmunotherapyprostaglandin

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