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Abstract
γδT cell receptors (γδTCRs) recognize a broad range of malignantly transformed cells in mainly a major histocompatibility complex (MHC)-independent manner, making them valuable additions to the engineered immune effector cell therapy that currently focuses primarily on αβTCRs and chimeric antigen receptors (CARs). As an exception to the rule, we have previously identified a γδTCR, which exerts antitumor reactivity against HLA-A*24:02-expressing malignant cells, however without the need for defined HLA-restricted peptides, and without exhibiting any sign of off-target toxicity in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse models. This particular tumor-HLA-A*24:02-specific Vγ5Vδ1TCR required CD8αα co-receptor for its tumor reactive capacity when introduced into αβT cells engineered to express a defined γδTCR (TEG), referred to as TEG011; thus, it was only active in CD8+ TEG011. We subsequently explored the concept of additional redirection of CD4+ T cells through co-expression of the human CD8α gene into CD4+ and CD8+ TEG011 cells, later referred as TEG011_CD8α. Adoptive transfer of TEG011_CD8α cells in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mice injected with tumor HLA-A*24:02+ cells showed superior tumor control in comparison to TEG011, and to mock control groups. The total percentage of mice with persisting TEG011_CD8α cells, as well as the total number of TEG011_CD8α cells per mice, was significantly improved over time, mainly due to a dominance of CD4+CD8+ double-positive TEG011_CD8α, which resulted in higher total counts of functional T cells in spleen and bone marrow. We observed that tumor clearance in the bone marrow of TEG011_CD8α-treated mice associated with better human T cell infiltration, which was not observed in the TEG011-treated group. Overall, introduction of transgenic human CD8α receptor on TEG011 improves antitumor reactivity against HLA-A*24:02+ tumor cells and further enhances in vivo tumor control.
Highlights
GdT cells share the properties of both innate and adaptive immunity and play an essential role in cancer immunosurveillance [1, 2]
We investigated whether introduction of CD8aa or CD8ab along with Vg5Vd1TCR derived from clone FE11 could enhance antitumor reactivity of CD8+, and functionally reprogram CD4+ TEG011 cells
While TEG011 has shown a favorable efficacy profile in vivo, we only observed in approximately 50% of the mice long-term persistence of CD8+ TEG011 cells, which could be due to the lack of support by antigen-specific CD4+ T cells [29, 40]
Summary
GdT cells share the properties of both innate and adaptive immunity and play an essential role in cancer immunosurveillance [1, 2]. Unlike conventional abT cells, gdT cells recognize their cognate antigens in an MHC-unrestricted manner, targeting stress-induced and malignantly transformed self-antigens [3, 4]. GdT cells represent an attractive cell subset to substantiate T cell-based immunotherapeutic strategies that still mainly focus on abT cells. Based on their TCRd chain repertoire, two major subsets of gdT cells can be distinguished: Vd2+ and Vd2− cells. Vd2− cells mainly localize in mucosal and epithelial tissues, but their antitumor properties are scarcely known [4]. Vd2− cells recognize a broad range of stress-induced ligands, such as the MHC-associated proteins MICA and MICB, foreign lipid antigens presented on CD1c/d molecules in classical
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