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PD‑L1 mediates triple‑negative breast cancer evolution via the regulation of TAM/M2 polarization.

ABSTRACT: Tumor‑associated macrophages/M2‑type (TAM/M2) play a key role in the metastasis and angiogenesis of cancer, and are considered to be critical targets for cancer treatment. However, it remains unclear whether α‑programmed death‑ligand 1 (αPD‑L1; PD‑L1 inhibitor) inhibits tumor progression via targeting TAMs. In the present study, it was demonstrated that αPD‑L1 significantly inhibited IL‑13‑induced TAM/M2 polarization in vitro. Moreover, αPD‑L1 inhibited the epithelial‑mesenchymal transition (EMT) process and the stemness of triple‑negative breast cancer (TNBC) cells, which were mediated via the reversal of TAM/M2 polarization. This therefore inhibited the migration and angiogenesis of TNBC cells. Furthermore, αPD‑L1 prevented STAT3 phosphorylation and nuclear translocation, which resulted in the arrest of TAM/M2 polarization. In vivo experiments further demonstrated that αPD‑L1 reduced the number of lung metastases without affecting tumor growth. Moreover, αPD‑L1 reduced the expression levels of TAM/M2, EMT, stemness and vascular markers in tumor tissues. In summary, these data suggest that αPD‑L1 plays a vital role in the anti‑metastasis and anti‑angiogenesis of TNBC in vitro and in vivo via the inhibition of TAM/M2 polarization. These findings may thus provide a novel therapeutic strategy for clinically refractory TNBC.

SUBMITTER: Meng Z

PROVIDER: S-EPMC9591321 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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PD‑L1 mediates triple‑negative breast cancer evolution via the regulation of TAM/M2 polarization.

Meng Ziqi Z Zhang Rui R Wu Xuwei X Zhang Meihua M Jin Tiefeng T

International journal of oncology 20221020 6

Tumor‑associated macrophages/M2‑type (TAM/M2) play a key role in the metastasis and angiogenesis of cancer, and are considered to be critical targets for cancer treatment. However, it remains unclear whether α‑programmed death‑ligand 1 (αPD‑L1; PD‑L1 inhibitor) inhibits tumor progression via targeting TAMs. In the present study, it was demonstrated that αPD‑L1 significantly inhibited IL‑13‑induced TAM/M2 polarization <i>in vitro</i>. Moreover, αPD‑L1 inhibited the epithelial‑mesenchymal transiti ...[more]

PMID: 36263619

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Project description:The present work was an endeavor to shed light on how mild photothermia possibly synergizes with immune checkpoint inhibition for tumor therapy. We established mild photothermal heating protocols to generate temperatures of 43 °C and 45 °C in both in vitro and in vivo mouse 4T1 triple-negative breast cancer (TNBC) models using polyglycerol-coated carbon nanohorns (CNH-PG) and 808 nm laser irradiation. Next, we found that 1) CNH-PG-mediated mild photothermia (CNH-PG-mPT) significantly increased expression of the immune checkpoint PD-L1 and type-1 macrophage (M1) markers in the TNBC tumors; 2) CNH-PG-mPT had a lower level of anti-tumor efficacy which was markedly potentiated by BMS-1, a PD-L1 blocker. These observations prompted us to explore the synergetic mechanisms of CNH-PG-mPT and BMS-1 in the context of tumor cell-macrophage interactions mediated by PD-L1 since tumor-associated macrophages (TAMs) are a major source of PD-L1 expression in tumors. In vitro, the study then identified two dimensions where BMS-1 potentiated CNH-PG-mPT. First, CNH-PG-mPT induced PD-L1 upregulation in the tumor cells and showed a low level of cytotoxicity which was potentiated by BMS-1. Second, CNH-PG-mPT skewed TAMs towards an M1-like anti-tumor phenotype with upregulated PD-L1, and BMS-1 bolstered the M1-like phenotype. The synergistic effects of BMS-1 and CNH-PG-mPT both on the tumor cells and TAMs were more pronounced when the two cell populations were in co-culture. Further in vivo study confirmed PD-L1 upregulation both in tumor cells and TAMs in the TNBC tumors following treatment of CNH-PG-mPT. Significantly, TAMs depletion largely abolished the anti-TNBC efficacy of CNH-PG-mPT alone and in synergy with BMS-1. Collectively, our findings reveal PD-L1 upregulation to be a key response of TNBC to mild photothermal stress, which plays a pro-survival role in the tumor cells while also acting as a brake on the M1-like activation of the TAMs. Blockade of mPT‑induced PD‑L1 achieves synergistic anti-TNBC efficacy by taking the intrinsic survival edge off the tumor cells on one hand and taking the brakes off the M1-like TAMs on the other. Our findings reveal a novel way (i.e. mild thermia plus PD-L1 blockade) to modulate the TAMs-tumor cell interaction to instigate a mutiny of the TAMs against their host tumor cells.

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

PD‑L1 mediates triple‑negative breast cancer evolution via the regulation of TAM/M2 polarization.

Publications

PD‑L1 mediates triple‑negative breast cancer evolution via the regulation of TAM/M2 polarization.

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