Soluble HLA-G Inhibits Cell Cycle Progression in Human Alloreactive T Lymphocytes

Bahri, Rajia; Hirsch, François; Josse, Adeline; Rouas‐Freiss, Nathalie; Bidère, Nicolas; Vasquez, A. Cecilia; Carosella, Edgardo D.; Charpentier, B; Dürrbach, Antoine

doi:10.4049/jimmunol.176.3.1331

Cited by 121 publications

(61 citation statements)

References 38 publications

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“…Also, HLA-G peptide vaccine would not be suitable for autoimmune patients because it could aggravate their disease in instances where HLA-G is expressed. 25 Homologous sequences very similar to HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] were found on the classical MHC-I HLA-A, -B and -C molecules (Table S1). Nevertheless, the HLA-G 26-40 -specific CD4 C T cells did not crossreact with these analogous peptides.…”

Section: Discussionmentioning

confidence: 99%

“…reactivity, our results and the restricted expression of HLA-G indicate that T cell responses to HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] would not results in widespread autoimmunity when used in the clinical setting. Moreover, we found a substantial amount of IFNg production from patient PBMCs by HLA-G [25][26][27][28][29][30][31][32][33] peptide stimulation suggesting that this peptide can potentially induce Th1 rather than regulatory T cells. However, recent studies show that the polarization of CD4 C T cell is independent of the peptide sequence 26 and thus the combinatorial use of Th1-skewed adjuvants will be important for a peptide vaccine to polarize CD4 C T cells into Th1 cells instead of T regulatory cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, HLA-G downregulates the effector function of NK cells, CTLs and CD4 C T cells through its interaction with the KIR2DL4 and ILT2 receptors. [29][30][31][32][33][34][35] Interestingly, in some circumstances, DCs express HLA-G after they acquire a regulatory function by interacting with tumor-derived MUC1. 36,37 From this perspective, it is possible that an HLA-G 26-40 vaccine could target regulatory DCs in addition to HLA-G expressing tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Next, we determined the HLA class II molecules presenting HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] to the four CD4 C T cell clones. We first evaluated the capacity of anti-HLA-DR mAbs (or anti-class I mAbs, as negative control) to inhibit T cell responses to peptide-pulsed autologous PBMCs.…”

Section: In Vitro Induction Of Hla-g-specific Cd4 C T Cell Responsesmentioning

confidence: 99%

“…4A, the HLA-G-specific CD4 C T cell clones directly recognized the HLA-DR subtype-matched tumor cells expressing HLA-G when the cell lines were treated with IFNg (Lu65, did not have to be treated with IFNg, to be recognized by the CD4 C T cell clones). The T cell response against the tumor cells was effectively inhibited by anti-HLA-DR mAb, indicating that HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was presented in the context of HLA-DR. Treatment with 5-AZA increased the T cell responses to the HLA-G-expressing tumors except for Lu65 (Fig.…”

Section: Hla-g Tumor Expression Is Enhanced By Ifng and Dna Methyltramentioning

confidence: 99%

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Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

et al. 2016

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(2016) Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy, OncoImmunology, 5:6, e1169356 ABSTRACTTumor immune escape has been a major problem for developing effective immunotherapy. The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule whose primary function is to protect the fetus from the mother's immune system. While HLA-G is hardly found in normal adult tissues, various tumor cells are known to express it, aiding their escape from the immune system. Thus, HLA-G is an attractive immunotherapy target. CD4 C helper T lymphocytes (HTLs) play an important role in the immune reaction against tumors by assisting in the generation and persistence of CD8 C cytotoxic T lymphocytes (CTLs) or by displaying direct antitumor effects. We report here that HLA-G expression in breast cancer significantly correlates with a poor prognosis. Also, we describe that the MHC class II-binding peptide HLA-G 26-40 was effective in eliciting tumor-reactive CD4 C T cell responses. Furthermore, treatment with the DNA methyltransferase inhibitor 5-aza-2 0 -deoxycytidine increased HLA-G expression in tumors and subsequently enhanced recognition by HLA-G 26-40 -specific HTLs. These findings predict that a combination immunotherapy targeting HLA-G together with a DNA methyltransferase inhibitor could be useful against some cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: In Vitro Induction Of Hla-g-specific Cd4 C T Cell Responsesmentioning

confidence: 99%

Section: Hla-g Tumor Expression Is Enhanced By Ifng and Dna Methyltramentioning

confidence: 99%

See 3 more Smart Citations

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

et al. 2016

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In vivo evidence that secretion of HLA‐G by immunogenic tumor cells allows their evasion from immunosurveillance

Loumagne

Baudhuin

Favier

et al. 2014

Intl Journal of Cancer

Self Cite

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Human leukocyte antigen‐G (HLA‐G) expression by tumors has been evidenced in numerous malignancies in association with poor prognosis and resistance to immunotherapy in humans. Particularly, soluble form of HLA‐G was measured at high concentrations in malignant effusions and plasma from cancer patients, and inhibits antitumor immune cells in vitro through interaction with immunoglobulin‐like transcript (ILT) receptors. Nevertheless, in vivo study demonstrating that HLA‐G secretion by tumor cells allows their escape from immunosurveillance remained to be established. Despite nondescribed murine homolog, direct functional interaction of HLA‐G with murine paired immunoglobulin‐like receptor (PIR)‐B, ortholog of human ILT receptors, enables to investigate its role in vivo. Immunocompetent mice were injected either with syngeneic tumor cells co‐expressing HLA‐G5, the main soluble HLA‐G isoform, and the conformation stabilizer human β2‐microglubulin (hβ2m), or with hβ2m+HLA‐G5− tumor cells. hβ2m expressed at both tumor cell surface acted as a tumor antigen triggering a specific humoral response. Interestingly, although hβ2m+HLA‐G5− tumors were rejected, secreted HLA‐G5 provided hβ2m+HLA‐G5+ tumors a protection against hβ2m‐elicited immune rejection, enabling such immunogenic tumors to grow similarly to a poorly immunogenic tumor. HLA‐G5 tumor expression was associated with local and peripheral immunosuppression, characterized by dampened anti‐hβ2m B‐cell response, quantitative and functional T‐and B‐cell defects, accumulation of myeloid‐derived suppressor cells able to inhibit T‐cell proliferation and reduced T‐ and B‐cell tumor infiltrate. Our study provides the first in vivo proof that soluble HLA‐G counteracts tumor rejection and reinforces the importance to consider HLA‐G as a promising target to optimize current cancer immunotherapies.

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Generation of hypoimmunogenic human pluripotent stem cells via expression of membrane-bound and secreted β2m-HLA-G fusion proteins

Shi

Yang

et al. 2020

Stem Cells

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Allogeneic immune rejection is a major barrier for the application of human pluripotent stem cells (hPSCs) in regenerative medicine. A broad spectrum of immune cells, including T cells, natural killer (NK) cells, and antigen‐presenting cells, which either cause direct cell killing or constitute an immunogenic environment, are involved in allograft immune rejection. A strategy to protect donor cells from cytotoxicity while decreasing the secretion of inflammatory cytokines of lymphocytes is still lacking. Here, we engineered hPSCs with no surface expression of classical human leukocyte antigen (HLA) class I proteins via beta‐2 microglobulin (B2M) knockout or biallelic knockin of HLA‐G1 within the frame of endogenous B2M loci. Elimination of the surface expression of HLA class I proteins protected the engineered hPSCs from cytotoxicity mediated by T cells. However, this lack of surface expression also resulted in missing‐self response and NK cell activation, which were largely compromised by expression of β2m‐HLA‐G1 fusion proteins. We also proved that the engineered β2m‐HLA‐G5 fusion proteins were soluble, secretable, and capable of safeguarding low immunogenic environments by lowering inflammatory cytokines secretion in allografts. Our current study reveals a novel strategy that may offer unique advantages to construct hypoimmunogenic hPSCs via the expression of membrane‐bound and secreted β2m‐HLA‐G fusion proteins. These engineered hPSCs are expected to serve as an unlimited cell source for generating universally compatible “off‐the‐shelf” cell grafts in the future.

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Soluble HLA-G Inhibits Cell Cycle Progression in Human Alloreactive T Lymphocytes

Cited by 121 publications

References 38 publications

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

In vivo evidence that secretion of HLA‐G by immunogenic tumor cells allows their evasion from immunosurveillance

Generation of hypoimmunogenic human pluripotent stem cells via expression of membrane-bound and secreted β2m-HLA-G fusion proteins

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