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.
Highlights
Triple-negative breast cancer (TNBC; estrogen receptor a, progesterone receptor and HER2 (ERBB2)-negative) is the subtype of breast cancers with poorest prognosis due to lack of targeted therapies [1, 2]
The results showed that the level of programmed cell death 1-ligand 1 (PD-L1) and IDO1 were higher in TNBC than that in Luminal A positive breast cancer [42, 43] (Supplementary Figure 1)
Our findings showed that the expression of PD-L1 was positively correlated with IDO1 in TNBC patients from the data of Gene Expression Profiling Interactive Analysis (GEPIA) RNAsequencing, thereby implying that immunosuppressive effects dominated in this type of tumors and prevented normal T cell function
Summary
Triple-negative breast cancer (TNBC; estrogen receptor a, progesterone receptor and HER2 (ERBB2)-negative) is the subtype of breast cancers with poorest prognosis due to lack of targeted therapies [1, 2]. A study on breast cancer demonstrated that tumor-infiltrating gd T lymphocytes are correlated with a poor prognosis in human breast cancer patients (ER+, Her2+ positive) [6]. Another study showed that gd T cells infiltrated into various tumors, including TNBCs [7,8,9], and they appeared to be prognostically beneficial [10]. A possible explanation for this contradictory phenomenon was that accumulation of gd TILs in different breast cancer subtypes might be differently involved in microenvironment and resulted in different outcomes, which were mediated by unknown mechanisms
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