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Review
. 2024 Oct 3;73(12):253.
doi: 10.1007/s00262-024-03801-7.

GPCRs: emerging targets for novel T cell immune checkpoint therapy

Kaitlyn Dickinson  1 , Elliott J Yee  1 , Isaac Vigil  1 , Richard D Schulick  1 , Yuwen Zhu  2
Affiliations
Review

GPCRs: emerging targets for novel T cell immune checkpoint therapy

Kaitlyn Dickinson et al. Cancer Immunol Immunother. .

Abstract

Although immune checkpoint blockade (ICB) has become the mainstay of treatment for advanced solid organ malignancies, success in revitalizing the host anticancer immune response remains limited. G-protein coupled receptors (GPCRs) are a broad family of cell-surface proteins that have been regarded as main players in regulating the immune system, namely by mediating the activity of T lymphocytes. Among the most novel immunoregulatory GPCRs include GPR171, lysophosphatidic acid receptors (LPARs), GPR68, cannabinoid receptor 2 (CB2), and prostaglandin E receptors, many of which have shown promise in mediating antitumor response via activation of cytotoxic T cells, inhibiting immunosuppressive lymphocytes, and facilitating immune cell infiltration within the tumor microenvironment across multiple types of cancers. This paper reviews our current understanding of some of the most novel GPCRs-their expression patterns, evolving roles within the immune system and cancer, potential therapeutic applications, and perspective for future investigation.

Keywords: GPCRs; Immune checkpoint inhibitor; T cell; Tumor immunology.

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Conflict of interest statement

R.D.S and Y.Z. are coinventors of a patent licensed to DynamiCure (managed by the University of Colorado) outside the submitted work. Y.Z. consults for DynamiCure Biotechnology. All other authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Summary of GPCR signaling modulating CD8 + T cell activity. SPC, sphingosylphosphorylcholine; OGR1, ovarian cancer GPCR 1; NAGly, N-arachidonyl glycine; A2AR, adenosine A2A receptor; LPAR, lysophosphatidic acid receptor; LPA, lysophosphatidic acid; Tim-3, T cell immunoglobulin and mucin domain-containing protein 3; PD-1, programmed cell death protein 1; ERK, extracellular signal-regulated kinase; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; cAMP, cyclic adenosine monophosphate
Fig. 2
Fig. 2
Summary of GPCR signaling modulating CD4 + T cell activity. 2-AG, 2-arachidonoylglycerol; THC, 9-tetrahydrocannabinol; AEA, anandamide; CB2, cannabinoid receptor 2; LysoPS, lysophosphatidylserine; LPA, lysophosphatidic acid; ATP, adenosine triphosphate; S1P, sphingosine-1-phosphate; LPA, lysophosphatidic acid; PGE2, prostaglandin E2; EP2, prostaglandin receptor 2; CCL, chemokine ligand; CXCL, chemokine (C-X-C motif) ligand; Treg, T regulatory cell; ROCK2, Rho-associated coiled-coil containing protein kinase 2; TNF, tumor necrosis factor
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