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Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer.

ABSTRACT: Programmed cell death 1 (PD-1) is widely expressed in tumor-infiltrating lymphocytes (TILs) of triple-negative breast cancer (TNBC). As a dominant inhibitory immune checkpoint (ICP) receptor, cell surface PD-1 is well-known to transduce negative signaling of effector T cell activity during cell-cell contact. However, despite its well-documented inhibitory effects, higher PD-1 expression in TILs is significantly associated with longer survival in TNBC patients. This phenomenon raises an interesting question whether PD-1 harbors positive activity to enhance anti-tumor immunity. Here, we show that PD-1 is secreted in an exosomal form by activated T cells and can remotely interact with either cell surface or exosomal programmed death-ligand 1 (PD-L1), induce PD-L1 internalization via clathrin-mediated endocytosis, and thereby prevent subsequent cellular PD-L1: PD-1 interaction, restoring tumor surveillance through attenuating PD-L1-induced suppression of tumor-specific cytotoxic T cell activity. Our results, through revealing an anti-PD-L1 function of exosomal PD-1, provide a positive role to enhance cytotoxic T cell activity and a potential therapeutic strategy of modifying the exosome surface with membrane-bound inhibitory ICP receptors to attenuate the suppressive tumor immune microenvironment.

SUBMITTER: Qiu Y

PROVIDER: S-EPMC8342306 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer.

Qiu Yufan Y Yang Yi Y Yang Riyao R Liu Chunxiao C Hsu Jung-Mao JM Jiang Zhou Z Sun Linlin L Wei Yongkun Y Li Chia-Wei CW Yu Dihua D Zhang Jin J Hung Mien-Chie MC

Oncogene 20210625 31

Programmed cell death 1 (PD-1) is widely expressed in tumor-infiltrating lymphocytes (TILs) of triple-negative breast cancer (TNBC). As a dominant inhibitory immune checkpoint (ICP) receptor, cell surface PD-1 is well-known to transduce negative signaling of effector T cell activity during cell-cell contact. However, despite its well-documented inhibitory effects, higher PD-1 expression in TILs is significantly associated with longer survival in TNBC patients. This phenomenon raises an interesti ...[more]

PMID: 34172932

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Project description:PurposeProgrammed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor-immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1- TNBC.Experimental designFrom a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1+ and PD-L1- TNBC, as defined by FDA-approved PD-L1 companion assays.Results228 of 499 (46%) TNBC were PD-L1+ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1+ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation-related proteins correlated most strongly with PD-L1 protein.ConclusionsIn this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1+ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC.See related commentary by Symmans, p. 5446.

Project description:(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.

Dataset Information

Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer.

Publications

Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer.

Similar Datasets

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