Abstract
Phenotypic characterization of γδ T cells in the MALs (malignant ascites lymphocytes), TILs (tumor infiltrating lymphocytes), and PBLs (peripheral blood lymphocytes) of ovarian cancer (OvCA) patients is lacking. Therefore, we quantified γδ T cell prevalence in MAL, TIL, and PBL specimens from n = 18 OvCA patients and PBL from age-matched healthy donors (HD, n = 14). Multicolor flow cytometry was performed to evaluate the expression of inhibitory receptors (TIGIT, PD-1 and TIM-3), stimulatory receptors (Ox40), and purinergic ectoenzymes (CD39 and CD73) on γδ T cell subsets. We identified an abundant infiltration of Vδ1 T cells in the MALs and TILs. These cells varied in their differentiation: The majority of Vδ1 TILs displayed an effector memory (EM) phenotype, whereas Vδ1 MALs had a more mature phenotype of terminally differentiated effector memory cells (TEMRA) with high CD45RA expression. TIGIT and TIM-3 were abundantly expressed in both MALs and PBLs, whereas Vδ1 TILs exhibited the highest levels of PD-1, CD39, and Ox40. We also observed specific clusters on mature differentiation stages for the analyzed molecules. Regarding co-expression, Vδ1 TILs showed the highest levels of cells co-expressing TIGIT with PD-1 or CD39 compared to MALs and PBLs. In conclusion, the Vδ1 T cell population showed a high prevalence in the MALs and primary tumors of OvCA patients. Due to their (co-)expression of targetable immune receptors, in particular TIGIT with PD-1 and CD39 in TILs, Vδ1 T cell-based approaches combined with the inhibition of these targets might represent a promising strategy for OvCA.
Highlights
According to the SEER data base, ovarian cancer (OvCA) ranks fifth in cancer deaths among women with a rate of new cases of 10.9 per 100,000 and a death rate of 6.5 per 100,000
T cell Ig and ITIM domain (TIGIT), PD-1, CD39, and Ox40 emerged as molecules of interest
We observed an increased proportion of TIGIT+, TIM-3+, and Ox40+ Vδ1 T cells in PBLs from OvCA patients compared to HD PBLs (p = 0.0004, p = 0.072, p = 0.010, respectively; Figure 3A)
Summary
According to the SEER data base, ovarian cancer (OvCA) ranks fifth in cancer deaths among women with a rate of new cases of 10.9 per 100,000 and a death rate of 6.5 per 100,000. NKRs bind to surface proteins associated with disease or stress conditions on (malignant) cells [5] These features make them independent of immune evasion mechanisms including downregulation of MHC presentation and of mutated epitopes [6–8]. Initial clinical trials are already testing γδ T cell-based chimeric antigen receptor T cells (CAR-T cells) or bispecific T cell engagers (BiTEs) [6], the expression of co-inhibitory targets on γδ T cells has been barely explored to this day. This knowledge may shed light onto their state of activation and exhaustion. Identification of checkpoint molecules may identify targets restoring γδ T cell-mediated cytotoxicity
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