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The HLA-G immune checkpoint: a new immuno-stimulatory role for the α1-domain-deleted isoform

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Abstract

The heterogeneity of cancer cells, in part maintained via the expression of multiple isoforms, introduces significant challenges in designing effective therapeutic approaches. In this regard, isoforms of the immune checkpoint HLA-G have been found in most of the tumors analyzed, such as ccRCC, the most common human renal malignancy. In particular, HLA-G∆α1, which is the only HLA-G isoform described that lacks the α1 extracellular domain, has been newly identified in ccRCC and now here in trophoblasts. Using a cellular model expressing HLA-G∆α1, we have uncovered its specific and overlapping functional roles, relative to the main HLA-G isoform, i.e., the full-length HLA-G1. We found that HLA-G∆α1 has several particular features: (i) although possessing the α3 domain, it does not associate with β2-microglobulin; (ii) it may not present peptides to T cells due to absence of the peptide-binding groove; and (iii) it exerts immune-stimulatory activity towards peripheral blood NK and T cells, while all known isoforms of HLA-G are immune-inhibitory checkpoint molecules. Such immune-stimulatory properties of HLA-G∆α1 on the cytotoxic function of peripheral blood NK cells are individual dependent and are not exerted through the interaction with the known HLA-G receptor, ILT2. Importantly, we are faced here with a potential antitumor effect of an HLA-G isoform, opposed to the pro-tumor properties described for all other HLA-G isoforms, which should be taken into account in future therapeutic designs aimed at blocking this immune checkpoint.

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Acknowledgements

The authors are particularly grateful to Dr. S. Ferrone (USA) who kindly provided the anti-HLA class I CR10-215 antibody and to Raluca Stanciu for experimental help on trophoblast analysis.

Funding

This work was supported by the Institut National du Cancer (INCA, PRTK-2018 OncoTheraGe), the Atomic Energy and Alternative Energies Agency (CEA) and the University of Paris, France.

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Authors and Affiliations

  1. Atomic Energy and Alternative Energies Agency (CEA), Hematology and Immunology Research Division, Saint-Louis Hospital, 1, avenue Claude Vellefaux, 75010, Paris, France

    Diana Tronik-Le Roux, Marina Daouya, Alix Jacquier, Chantal Schenowitz, François Desgrandchamps, Nathalie Rouas-Freiss & Edgardo D. Carosella

  2. IRSL, UMRS 976, HIPI Unit, University of Paris, Paris, France

    Diana Tronik-Le Roux, Marina Daouya, Alix Jacquier, Chantal Schenowitz, François Desgrandchamps, Nathalie Rouas-Freiss & Edgardo D. Carosella

  3. Service d’Urologie, AP-HP, Hôpital Saint-Louis, Paris, France

    François Desgrandchamps

Authors
  1. Diana Tronik-Le Roux
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  2. Marina Daouya
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  3. Alix Jacquier
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  4. Chantal Schenowitz
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  6. Nathalie Rouas-Freiss
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  7. Edgardo D. Carosella
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Contributions

Conceptualization: DT-LR; NR-F, EDC. Methodology: MD, AJ, CS. Formal analysis and investigation: DT-LR; MD, NR-F, EDC. Writing—original draft preparation: DT-LR; NR-F. Resources: FD; DT-LR. Supervision: DT-LR; NR-F, EDC.

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Correspondence to Diana Tronik-Le Roux.

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Tronik-Le Roux, D., Daouya, M., Jacquier, A. et al. The HLA-G immune checkpoint: a new immuno-stimulatory role for the α1-domain-deleted isoform. Cell. Mol. Life Sci. 79, 310 (2022). https://doi.org/10.1007/s00018-022-04359-2

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  • DOI: https://doi.org/10.1007/s00018-022-04359-2

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