IDO Inhibition Facilitates Antitumor Immunity of Vγ9Vδ2 T Cells in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) escape from immune-mediated destruction was associated with immunosuppressive responses that dampened the activation of tumor-infiltrating CD8 and γδ T cells. TNBC had a higher level of programmed cell death 1-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO), compared with other breast cancer subtypes. But, clinical studies have revealed that the response rate of PD-1/PD-L1 antibody for TNBC treatment was relatively low. However, the antitumor responses of human Vγ9Vδ2 T cells or IDO inhibitor in TNBC treatment are unknown. In this study, we found that IDO1 and PD-L1 were highly expressed in TNBC patients. Analysis of the clinical samples demonstrated that Vγ9Vδ2 T cells became exhausted in triple-negative breast cancer patients. And Vγ9Vδ2 T cells combined with αPD-L1 could not further enhance their antitumor responses in vitro and in vivo. However, Vγ9Vδ2 T cells combined with IDO1 inhibitor 1-Methyl-L-tryptophan (1-MT) or Lindrostat showed substantial inhibitory effects on MDA-MB-231 tumor cells. Finally, we found that IDO1 inhibitor promoted T cell’s cytotoxicity by enhancing perforin production. These results converged to suggest the potential application of Vγ9Vδ2 T cells treated with IDO1 inhibitor for TNBC therapy.

Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands

“…Intriguingly, this in vivo differentiation was not a consequence of mechanisms induced by the immune system or the immunotherapy, since it was equally observed in immunodeficient mice with or without the presence of primary human γδ T cells. Xenografted cells exhibited increased surface expression of the inhibitory T cell ligands PD-L1 and PD-L2 compared to parental BCSC5 cells, in line with studies associating TNBC with high expression levels of the PD-L1 (Mittendorf et al 2014; Nanda et al 2016; Li et al 2021). This increased expression of inhibitory T cell ligands might explain the reduced susceptibility to be killed by γδ T cells.…”

“…However, a combinatorial treatment of xenografts with γδ T cells and α-PD-1 did not result in reduced xenograft growth. Similarly, Li and colleagues have described the inefficacy of this treatment regimen against TNBC MDA-MB-231-derived xenografts (Li et al 2021).…”

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

“…Mechanistically, increased IDO activity promotes tryptophan catabolism, leading to a depletion of this essential amino acid in the TME and to an accumulation of tryptophan metabolites such as kynurenine, which was shown to decrease γδ T-cell cytotoxic capacity [ 201 ]. As such, IDO inhibitors were shown to improve the cytotoxicity of Vγ9Vδ2 T cells against human pancreatic [ 201 ] and breast cancer cells [ 202 ]. These findings could be particularly relevant for patients with triple-negative breast cancer, of which only a minority benefited therapeutically from PD-1 blockade [ 203 ].…”

Androgens in Patients With Luminal B and HER2 Breast Cancer Might Be a Biomarker Promoting Anti-PD-1 Efficacy

“…A total of 35 sex- and age-matched healthy donors were enrolled from the medical examination department at the First Affiliated Hospital of Jinan University. PBMCs were collected from the patients with BRCA and healthy donors through the Ficoll-Paque (GE Healthcare) density gradient centrifugation protocol ( 34 ). The fresh serum and PBMCs were stored at −80°C, and tissue samples were fixed in formalin and embedded in paraffin.…”