Indoleamine 2,3-dioxygenase 1(IDO1) Regulates The Anti-tumor Immunity Of Vγ9vδ2 T Cells In Triple-negative Breast Cancer

Breast cancer is one of the most common types of malignant tumors in the female population.As a very malignant subtype of breast cancer,triple-negative breast cancer(TNBC)is still a difficult problem in basic research and clinical treatment,due to its lack of effective treatment target.Studies in recent years have found that immune checkpoint blockers,cell reinfusion therapy and other immunotherapies can effectively prolong the survival time of patients with advanced breast cancer.However,more and more clinical data show that the effect of single-agent immunotherapy is not satisfactory.We intend to further explore safer and more effective treatment options for triple-negative breast cancer,and provide new insights and guidance for solving the clinically low response and immune resistance of immunotherapy.In this study,the data of single-cell RNA-sequencing showed that indoleamine2,3-dioxygenase1(IDO1)and programmed cell death 1(PD-L1)are co-expressed in TNBC patients.Further analysis found that IDO1 was highest in tumor tissues of TNBC and lowest in Luminal A,while PD-L1 was not significantly different in tumor tissues and adjacent tissues of all breast cancer subtypes.We found that the PD-L1 and IDO1 levels of TNBC patients were higher than those of Luminal A patients through pathological tissue sections.A large number of RNA sequencing results show that the infiltration of γδ T cells may be related to the prognosis of TNBC patients and can be used as a prognostic marker for good survival.Due to the unique MHC-independent function of γδ T cells,it is of great clinical significance to explore the anti-tumor effect of the combined application of healthy human Vγ9Vδ2 T cells and PD-1/PD-L1 monoclonal antibodies or IDO1 inhibitors in TNBC.We revealed that Vγ9Vδ2 T cells combined with IDO1 inhibitor1-Methyl-L-tryptophan(1-MT)had substantial stronger therapeutic effects for TNBC based on in vivo and in vitro assay.Finally,we found that 1-MT promoted T cell’s cytotoxicity by enhancing perforin production.In conclusion,we propose a new method for the clinical treatment of TNBC that the combination of Vγ9Vδ2 T cells and IDO1 inhibitors is a safe and effective way for the treatment of TNBC.But it still needs to be verified in clinical trials.