AUTHOR=Brauneck Franziska , Weimer Pauline , Schulze zur Wiesch Julian , Weisel Katja , Leypoldt Lisa , Vohwinkel Gabi , Fritzsche Britta , Bokemeyer Carsten , Wellbrock Jasmin , Fiedler Walter 

TITLE=Bone Marrow-Resident Vδ1 T Cells Co-express TIGIT With PD-1, TIM-3 or CD39 in AML and Myeloma

JOURNAL=Frontiers in Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.763773

DOI=10.3389/fmed.2021.763773

ISSN=2296-858X

ABSTRACT=<p><bold>Background:</bold> γδ T cells represent a unique T cell subpopulation due to their ability to recognize cancer cells in a T cell receptor- (TCR) dependent manner, but also in a non-major histocompatibility complex- (MHC) restricted way via natural killer receptors (NKRs). Endowed with these features, they represent attractive effectors for immuno-therapeutic strategies with a better safety profile and a more favorable anti-tumor efficacy in comparison to conventional αβ T cells. Also, remarkable progress has been achieved re-activating exhausted T lymphocytes with inhibitors of co-regulatory receptors e.g., programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and of the adenosine pathway (CD39, CD73). Regarding γδ T cells, little evidence is available. This study aimed to immunophenotypically characterize γδ T cells from patients with diagnosed acute myeloid leukemia (AML) in comparison to patients with multiple myeloma (MM) and healthy donors (HD).</p><p><bold>Methods:</bold> The frequency, differentiation, activation, and exhaustion status of bone marrow- (BM) derived γδ T cells from patients with AML (<italic>n</italic> = 10) and MM (<italic>n</italic> = 11) were assessed in comparison to corresponding CD4<sup>+</sup> and CD8<sup>+</sup> T cells and peripheral blood- (PB) derived γδ T cells from HDs (<italic>n</italic> = 16) using multiparameter flow cytometry.</p><p><bold>Results:</bold> BM-infiltrating Vδ1 T cells showed an increased terminally differentiated cell population (TEMRAs) in AML and MM in comparison to HDs with an aberrant subpopulation of CD27<sup>−</sup>CD45RA<sup>++</sup> cells. TIGIT, PD-1, TIM-3, and CD39 were more frequently expressed by γδ T cells in comparison to the corresponding CD4<sup>+</sup> T cell population, with expression levels that were similar to that on CD8<sup>+</sup> effector cells in both hematologic malignancies. In comparison to Vδ2 T cells, the increased frequency of PD-1<sup>+</sup>-, TIGIT<sup>+</sup>-, TIM-3<sup>+</sup>, and CD39<sup>+</sup> cells was specifically observed on Vδ1 T cells and related to the TEMRA Vδ1 population with a significant co-expression of PD-1 and TIM-3 together with TIGIT.</p><p><bold>Conclusion:</bold> Our results revealed that BM-resident γδ T cells in AML and MM express TIGIT, PD-1, TIM-3 and CD39. As effector population for autologous and allogeneic strategies, inhibition of co-inhibitory receptors on especially Vδ1 γδ T cells may lead to re-invigoration that could further increase their cytotoxic potential.</p>