Tissue-Specific Expression of TIGIT, PD-1, TIM-3, and CD39 by γδ T Cells in Ovarian Cancer

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.

Update in TIGIT Immune-Checkpoint Role in Cancer

“…TIGIT and PD-1 high co-expression was observed in PBLs (peripheral blood lymphocytes), MALs (malignant ascites lymphocytes), and TILs with increased frequency in tumor proximity in matched samples of patients at first diagnosis of ovarian cancer not treated ( 129 ). Moreover, the authors also observed TIGIT and TIM3 co-expression in PBLs, MALs, and TILs but with a decreased frequency in tumor proximity ( 129 ).…”

The Role of TIM-3 and LAG-3 in the Microenvironment and Immunotherapy of Ovarian Cancer

“…In their paper, Weimer et al focus on the phenotypic characterization of γδ, Vδ1 and Vδ2 T cells in ovarian cancer. On all γδ, Vδ1 and Vδ2 T cells in PBLs, MALs and TILs from OC patients, they compared the expression levels of several co-regulatory receptors (CRRs), such as PD-1, TIM-3, Ox40, TIGIT (T cell immunoreceptor with Ig and ITIM domains), and two ectoenzymes CD39 and CD73 [ 28 ]. Previous findings have pointed out that PD-1 coexpression with TIM-3 or LAG-3 on T cells in patients with solid tumors is associated with immune exhaustion [ 28 , 29 ].…”

“…On all γδ, Vδ1 and Vδ2 T cells in PBLs, MALs and TILs from OC patients, they compared the expression levels of several co-regulatory receptors (CRRs), such as PD-1, TIM-3, Ox40, TIGIT (T cell immunoreceptor with Ig and ITIM domains), and two ectoenzymes CD39 and CD73 [ 28 ]. Previous findings have pointed out that PD-1 coexpression with TIM-3 or LAG-3 on T cells in patients with solid tumors is associated with immune exhaustion [ 28 , 29 ]. In their study, they demonstrated for the first time the expression of these checkpoints on phenotypically different Vδ1 cells in OC.…”

“…Their results indicate that the expression of TIM-3 and also TIGIT, PD-1, CD39 on Vδ1 cells differs among PBLs, MALs and TILs (tumor-infiltrating lymphocytes) in patients with OC and is dependent on interactions with the tumor microenvironment. In conclusion, this study demonstrated that the expression of TIGIT, PD-1 and CD39 was correlated with specific stages of Vδ1 T-cell maturation in OvCA [ 28 ].…”

γδ T cell exhaustion: Opportunities for intervention

“…Peripheral terminally differentiated Vδ2 T cells of breast cancer patients were demonstrated to display exhaustion phenotype with elevated PD‐1 expression, which was significantly associated with tumor‐draining lymph node invasion 42 . Recently, coexpression of PD‐1, Tim‐3, CD39 with TIGIT was reported on tumor‐infiltrating Vδ1 T cells in ovarian cancer, implying an increased state of exhaustion 43 . A majority of tumor‐infiltrating Vγ9 ‐ γδ T cells were detected in both lymphomas and solid tumors, which is quantitatively correlated with tissue residency and exhaustion and response to immune checkpoint therapy 44 .…”