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Mechanical strain induces phenotypic changes in breast cancer cells and promotes immunosuppression in the tumor microenvironment.

ABSTRACT: Breast cancer (BCa) proliferates within a complex, three-dimensional microenvironment amid heterogeneous biochemical and biophysical cues. Understanding how mechanical forces within the tumor microenvironment (TME) regulate BCa phenotype is of great interest. We demonstrate that mechanical strain enhanced the proliferation and migration of both estrogen receptor⁺ and triple-negative (TNBC) human and mouse BCa cells. Furthermore, a critical role for exosomes derived from cells subjected to mechanical strain in these pro-tumorigenic effects was identified. Exosome production by TNBC cells increased upon exposure to oscillatory strain (OS), which correlated with elevated cell proliferation. Using a syngeneic, orthotopic mouse model of TNBC, we identified that preconditioning BCa cells with OS significantly increased tumor growth and myeloid-derived suppressor cells (MDSCs) and M2 macrophages in the TME. This pro-tumorigenic myeloid cell enrichment also correlated with a decrease in CD8⁺ T cells. An increase in PD-L1⁺ exosome release from BCa cells following OS supported additive T cell inhibitory functions in the TME. The role of exosomes in MDSC and M2 macrophage was confirmed in vivo by cytotracking fluorescent exosomes, derived from labeled 4T1.2 cells, preconditioned with OS. In addition, in vivo internalization and intratumoral localization of tumor-cell derived exosomes was observed within MDSCs, M2 macrophages, and CD45-negative cell populations following direct injection of fluorescently-labeled exosomes. Our data demonstrate that exposure to mechanical strain promotes invasive and pro-tumorigenic phenotypes in BCa cells, indicating that mechanical strain can impact the growth and proliferation of cancer cell, alter exosome production by BCa, and induce immunosuppression in the TME by dampening anti-tumor immunity.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7686122 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mechanical strain induces phenotypic changes in breast cancer cells and promotes immunosuppression in the tumor microenvironment.

Wang Yong Y Goliwas Kayla F KF Severino Paige E PE Hough Kenneth P KP Van Vessem Derek D Wang Hong H Tousif Sultan S Koomullil Roy P RP Frost Andra R AR Ponnazhagan Selvarangan S Berry Joel L JL Deshane Jessy S JS

Laboratory investigation; a journal of technical methods and pathology 20200622 12

Breast cancer (BCa) proliferates within a complex, three-dimensional microenvironment amid heterogeneous biochemical and biophysical cues. Understanding how mechanical forces within the tumor microenvironment (TME) regulate BCa phenotype is of great interest. We demonstrate that mechanical strain enhanced the proliferation and migration of both estrogen receptor<sup>+</sup> and triple-negative (TNBC) human and mouse BCa cells. Furthermore, a critical role for exosomes derived from cells subjecte ...[more]

PMID: 32572176

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Project description:BACKGROUND:A significant challenge to overcome in pancreatic ductal adenocarcinoma (PDAC) is the profound systemic immunosuppression that renders this disease non-responsive to immunotherapy. Our supporting data provide evidence that CD200, a regulator of myeloid cell activity, is expressed in the PDAC microenvironment. Additionally, myeloid-derived suppressor cells (MDSC) isolated from patients with PDAC express elevated levels of the CD200 receptor (CD200R). Thus, we hypothesize that CD200 expression in the PDAC microenvironment limits responses to immunotherapy by promoting expansion and activity of MDSC. METHODS:Immunofluorescent staining was used to determine expression of CD200 in murine and human PDAC tissue. Flow cytometry was utilized to test for CD200R expression by immune populations in patient blood samples. In vivo antibody blocking of CD200 was conducted in subcutaneous MT-5 tumor-bearing mice and in a genetically engineered PDAC model (KPC-Brca2 mice). Peripheral blood mononuclear cells (PBMC) from patients with PDAC were analyzed by single-cell RNA sequencing. MDSC expansion assays were completed using healthy donor PBMC stimulated with IL-6/GM-CSF in the presence of recombinant CD200 protein. RESULTS:We found expression of CD200 by human pancreatic cell lines (BxPC3, MiaPaca2, and PANC-1) as well as on primary epithelial pancreatic tumor cells and smooth muscle actin+ stromal cells. CD200R expression was found to be elevated on CD11b+CD33+HLA-DRlo/- MDSC immune populations from patients with PDAC (p=0.0106). Higher expression levels of CD200R were observed in CD15+ MDSC compared with CD14+ MDSC (p<0.001). In vivo studies demonstrated that CD200 antibody blockade limited tumor progression in MT-5 subcutaneous tumor-bearing and in KPC-Brca2 mice (p<0.05). The percentage of intratumoral MDSC was significantly reduced in anti-CD200 treated mice compared with controls. Additionally, in vivo blockade of CD200 can also significantly enhance the efficacy of PD-1 checkpoint antibodies compared with single antibody therapies (p<0.05). Single-cell RNA sequencing of PBMC from patients revealed that CD200R+ MDSC expressed genes involved in cytokine signaling and MDSC expansion. Further, in vitro cytokine-driven expansion and the suppressive activity of human MDSC was enhanced when cocultured with recombinant CD200 protein. CONCLUSIONS:These results indicate that CD200 expression in the PDAC microenvironment may regulate MDSC expansion and that targeting CD200 may enhance activity of checkpoint immunotherapy.

Project description:Purpose The purpose of this study was to investigate the correlation between S100 calcium binding protein A9 (S100A9), tumour glycolysis and tumour infiltrating lymphocytes (TIL) in human epidermal growth factor receptor 2 (HER2) - positive breast cancer (BRCA). Materials and methods A total of 667 BRCA patients in Xiangya Hospital of Central South University were enrolled in this study. Haematoxylin and eosin (H&E) staining were used to count TIN in tissues. Human breast cancer cell lines (SK-BR-3 cells and BT474 cells) were transfected with S100A9 specific small interfering RNA (siRNA). The expressions of S100A9, glycolytic enzymes and lymphocyte markers were detected by immunohistochemistry (IHC) staining, Western blot and immunofluorescence. Lactate production, glucose consumption and the extracellular acidification rate (ECAR) were detected to assess glycolysis activity. Results S100A9 was significantly overexpressed in HER2+ cases. The expressions of phosphoglycerol kinase 1 (PGK1), lactate dehydrogenase A (LDHA) and enolase α (ENO1) were significantly up-regulated in S100A9 dominant tissues. The expressions of PGK1, LDHA and ENO1 detected in S100A9 silenced cell lines were significantly down-regulated. Moreover, S100A9 silencing significantly altered lactate production, glucose uptake and ECAR levels in HER2+ cell lines. Co-expression of S100A9 and c-Myc was detected in HER2+ tissues. The absence of S100A9 greatly hindered β-catenin expression in cell lines, which later induced the phosphorylation of c-Myc. The amount of TILs in cases with abundant S100A9 and LDHA was much greater than in cases with low S100A9 levels and poorer LDHA. TIL deficiency and elevated S100A9 intensity are factors affecting the survival rate of HER2+ BRCA cases. Conclusions S100A9 overexpression upregulated the glycolysis activity of tumour cells through the c-Myc-related pathway, suppressing lymphocyte infiltration in the tumour stroma, affecting the efficacy of immune regulation and long-term survival of patients.

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Mechanical strain induces phenotypic changes in breast cancer cells and promotes immunosuppression in the tumor microenvironment.

Publications

Mechanical strain induces phenotypic changes in breast cancer cells and promotes immunosuppression in the tumor microenvironment.

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