Regulatory T Cells Support Breast Cancer Progression by Opposing IFN-γ-Dependent Functional Reprogramming of Myeloid Cells

Clark, Nicholas; Martinez, Leandro Marcelo; Murdock, Steven; DeLigio, James T.; Olex, Amy L.; Effi, Comfort; Dozmorov, Mikhail G.; Bos, Paula D.

doi:10.1016/j.celrep.2020.108482

Cited by 31 publications

(27 citation statements)

References 58 publications

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“…Regarding the expression of OX40, the author Hamidinia M et al 50 observed that CD4 + T lymphocytes expressing OX40 exerted antitumor activity and a better prognosis in patients with BC. Fu Y et al 51 announced that the immunosuppressive action of Tregs could be reversed through an increase in the expression of OX40.…”

Section: Discussionmentioning

confidence: 99%

Circulating immune biomarkers in peripheral blood correlate with clinical outcomes in advanced breast cancer

Palazón‐Carrión

Jiménez‐Cortegana

Sánchez-León

et al. 2021

Sci Rep

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Identification of the different elements intervening at the tumor microenvironment seems key to explain clinical evolution in several tumor types. In this study, a set of immune biomarkers (myeloid derived suppressor cells, regulatory T cells, and OX40 + and PD-1 + T lymphocytes counts) in peripheral blood of patients diagnosed with advanced breast cancer were analyzed along of first line antineoplastic therapy. Subsequently, a comparison between groups with clinical benefit versus progression of disease and with a healthy women cohort was executed. Results reflected that patients showed higher basal levels of myeloid derived suppressor cells (35.43, IR = 180.73 vs 17.53, IR = 16.96 cells/μl; p = 0.001) and regulatory T cells (32.05, IR = 29.84 vs 22.61, IR = 13.57 cells/μl; p = 0.001) in comparison with healthy women. Furthermore, an increase in the number of activated T lymphocytes (expressing OX40), a decrease of immune inhibitory cells (MDSCs and Tregs) and inhibited T lymphocytes (expressing PD-1) were observed along the treatment in patients with clinical benefit (p ≤ 0.001). The opposite trend was observed in the case of disease progression. These findings suggest that some critical immune elements can be easily detected and measured in peripheral blood, which open a new opportunity for translational research, as they seem to be correlated with clinical evolution, at least in ABC.

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Section: Discussionmentioning

confidence: 99%

Circulating immune biomarkers in peripheral blood correlate with clinical outcomes in advanced breast cancer

Palazón‐Carrión

Jiménez‐Cortegana

Sánchez-León

et al. 2021

Sci Rep

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“…40 In our study, blocking N-cadherin or downregulating IL-8 attenuated the metabolic advantage and the immunosuppression caused by eTreg cells. However, there are some limitations to acknowledge: (1) how N-cadherin regulates FFA production is unknown and requires further research in prostate cancer; (2) if Tregs have reduced proliferation or survival, differential homing, or distinct differentiation, among other possibilities, still requires further research in the future; and (3) the impact of N-cadherin on Treg also been reported in other cancers 55 and may need further research in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells

Sun

Jing

et al. 2021

J Immunother Cancer

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BackgroundFew patients with prostate cancer benefit from current immunotherapies. Therefore, we aimed to explore new strategies to change this paradigm.MethodsHuman tissues, cell lines and in vivo experiments were used to determine whether and how N-cadherin impacts the production of programmed death ligand-1 (PD-L1) and indole amine 2,3-dioxygenase (IDO-1) and whether N-cadherin can increase the production of effector (e)Treg cells. Then, we used PC3-bearing humanized non-obese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice with an intravenous injection of human CD34+ hematopoietic stem cells into the tail vein to evaluate whether the N-cadherin antagonist N-Ac-CHAVC-NH2 (designated ADH-1) could improve the therapeutic effect of tumor-infiltrating lymphocyte (TIL)-related treatment.ResultsN-cadherin dramatically upregulated the expression of PD-L1 and IDO-1 through IFN-γ (interferongamma) signaling and increasing the production of free fatty acids that could promote the generation of eTreg cells. In preclinical experiments, immune reconstitution mediated by TILs slowed tumor growth and extended the survival time; however, this effect disappeared after immune system suppression by PD-L1, IDO-1 and eTreg cells. Furthermore, ADH-1 effectively reduced immunosuppression and enhanced TIL-related therapy.ConclusionsThese data show that the N-cadherin antagonist ADH-1 promotes TIL antitumor responses. This important hurdle must be overcome for tumors to respond to immunotherapy.

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“…Analysis of tumors in the TCGA and METABRIC databases suggested that ER+ cancers were more likely to express an M2 signature than TNBCs, which displayed higher M1 polarization [66], supported by single-cell RNA sequencing analyses [80]. Among the patients with ER+ disease, tumors where macrophages predominantly expressed an M1 phenotype had a better prognosis [81], whereas the M2 marker, CD163, was associated with poorer survival [55,82]. Interestingly, outcomes of crosstalk between TNBC and ER+ tumor cell lines and monocytes in defined in vitro systems were qualitatively distinct [83,84].…”

Section: Immune Microenvironment Of Primary Er+ Tumorsmentioning

confidence: 92%

Endogenous and Therapeutic Estrogens: Maestro Conductors of the Microenvironment of ER+ Breast Cancers

Schuler

Murdoch

2021

Cancers

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Estrogen receptor alpha (ERα) marks heterogeneous breast cancers which display a repertoire of somatic genomic mutations and an immune environment that differs from other breast cancer subtypes. These cancers also exhibit distinct biological behaviors; despite an overall better prognosis than HER2+ or triple negative breast cancers, disseminated dormant cells can lead to disease recurrence decades after the initial diagnosis and treatment. Estrogen is the best studied driver of these cancers, and antagonism or reduction of estrogen activity is the cornerstone of therapeutic approaches. In addition to reducing proliferation of ERα+ cancer cells, these treatments also alter signals to multiple other target cells in the environment, including immune cell subpopulations, cancer-associated fibroblasts, and endothelial cells via several distinct estrogen receptors. In this review, we update progress in our understanding of the stromal cells populating the microenvironments of primary and metastatic ER+ tumors, the effects of estrogen on tumor and stromal cells to modulate immune activity and the extracellular matrix, and net outcomes in experimental and clinical studies. We highlight new approaches that will illuminate the unique biology of these cancers, provide the foundation for developing new treatment and prevention strategies, and reduce mortality of this disease.

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Regulatory T Cells Support Breast Cancer Progression by Opposing IFN-γ-Dependent Functional Reprogramming of Myeloid Cells

Cited by 31 publications

References 58 publications

Circulating immune biomarkers in peripheral blood correlate with clinical outcomes in advanced breast cancer

Circulating immune biomarkers in peripheral blood correlate with clinical outcomes in advanced breast cancer

N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells

Endogenous and Therapeutic Estrogens: Maestro Conductors of the Microenvironment of ER+ Breast Cancers

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