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Identification of a tumor-specific allo-HLA-restricted ??TCR.

ABSTRACT: ??T cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how ??T-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8?-dependent V?5V?1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of ??TCRs, we show that classic anti-HLA-directed, ??TCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive ??T-cell repertoires provide therapeutic opportunities, either within the context of haplotransplantation or as individual ??TCRs for genetic engineering of tumor-reactive T cells.

SUBMITTER: Kierkels GJJ

PROVIDER: S-EPMC6784524 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Identification of a tumor-specific allo-HLA-restricted γδTCR.

Kierkels G J J GJJ Scheper W W Meringa A D AD Johanna I I Beringer D X DX Janssen A A Schiffler M M Aarts-Riemens T T Kramer L L Straetemans T T Heijhuurs S S Leusen J H W JHW San José E E Fuchs K K Griffioen M M Falkenburg J H JH Bongiovanni L L de Bruin A A Vargas-Diaz D D Altelaar M M Heck A J R AJR Shultz L D LD Ishikawa F F Nishimura M I MI Sebestyén Z Z Kuball J J

Blood advances 20191001 19

γδT cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how γδT-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8α-dependent Vγ5Vδ1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fractio ...[more]

PMID: 31585951

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Project description:NY-ESO-1 is a tumor-specific, highly immunogenic, human germ cell antigen of the MAGE-1 family that is a promising vaccine and cell therapy candidate in clinical trial development. The mouse genome does not encode an NY-ESO-1 homolog thereby not subjecting transgenic T-cells to thymic tolerance mechanisms that might impair in-vivo studies. We hypothesized that an NY-ESO-1 T cell receptor (TCR) transgenic mouse would provide the unique opportunity to study avidity of TCR response against NY-ESO-1 for tumor vaccine and cellular therapy development against this clinically relevant and physiological human antigen. To study in vitro and in vivo the requirements for shaping an effective T cell response against the clinically relevant NY-ESO-1, we generated a C57BL/6 HLA-A*0201 background TCR transgenic mouse encoding the 1G4 TCR specific for the human HLA-A2 restricted, NY-ESO-1157-165 SLLMWITQC (9C), initially identified in an NY-ESO-1 positive melanoma patient. The HLA-A*0201 restricted TCR was positively selected on both CD4+ and CD8+ cells. Mouse 1G4 T cells were not activated by endogenous autoimmune targets or a large library of non-cognate viral antigens. In contrast, their activation by HLA-A2 NY-ESO-1157-165 complexes was evident by proliferation, CD69 upregulation, interferon-γ production, and interleukin-2 production, and could be tuned using a twofold higher affinity altered peptide ligand, NY-ESO-1157-165V. NY-ESO-1157-165V recombinant vaccination of syngeneic mice adoptively transferred with m1G4 CD8+ T cells controlled tumor growth in vivo. 1G4 transgenic mice suppressed growth of syngeneic methylcholanthrene (MCA) induced HHD tumor cells expressing the full-length human NY-ESO-1 protein but not MCA HHD tumor cells lacking NY-ESO-1. The 1G4 TCR mouse model for the physiological human TCR against the clinically relevant antigen, NY-ESO-1, is a valuable tool with the potential to accelerate clinical development of NY-ESO-1-targeted T-cell and vaccine therapies.

Dataset Information

Identification of a tumor-specific allo-HLA-restricted ??TCR.

Publications

Identification of a tumor-specific allo-HLA-restricted γδTCR.

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