Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we descri... more Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we describe a novel mechanism by which mesenchymal stem cell (MSC)-derived exosomes drive an immunosuppressive program within the breast tumor microenvironment. Initial q-PCR and immunophenotyping of human breast tumor samples, and TCGA data analysis confirmed a positive correlation between infiltrations of MSC and M2 macrophage phenotype, therefore we hypothesized that MSC promote M2 macrophage differentiation in breast tumors. We then performed a series of experiments in vitro and in vivo, and found that MSC-derived exosomes significantly promote differentiation of macrophages into PD-L1 expressing ‘M2-like’ phenotype, while also enhancing malignant progression of breast tumors, in vivo. Additionally, we observed increased invasive potential of tumor cells with higher expression of mesenchymal markers when induced with MSC-derived exosomes. Importantly, our observation of a significantly higher TGF-β production by tumor associated macrophages in exosome-induced tumors, with stronger PD-1 expression by intra-tumoral T cells, suggests TGF-β driven PD-1 upregulation. Blocking of PD-L1 abrogates exosome-induced tumor growth signifying the PD-L1/PD-1 checkpoint pathway is vital to MSC-induced tumor progression. Together, infiltration of MSCs within breast tumors drives the increased invasive potential as well as immune-checkpoint-mediated immunosuppression through inducing PD-L1 expression by tumor associated macrophages and PD-1 expression by T cells. Targeting infiltration of MSCs into the breast tumor therefore is a potential approach to reduce breast tumor metastases and improve efficacy of immunotherapies.
Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we descri... more Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we describe a novel mechanism by which mesenchymal stem cell (MSC)-derived exosomes drive an immunosuppressive program within the breast tumor microenvironment. Initial q-PCR and immunophenotyping of human breast tumor samples, and TCGA data analysis confirmed a positive correlation between infiltrations of MSC and M2 macrophage phenotype, therefore we hypothesized that MSC promote M2 macrophage differentiation in breast tumors. We then performed a series of experiments in vitro and in vivo, and found that MSC-derived exosomes significantly promote differentiation of macrophages into PD-L1 expressing ‘M2-like’ phenotype, while also enhancing malignant progression of breast tumors, in vivo. Additionally, we observed increased invasive potential of tumor cells with higher expression of mesenchymal markers when induced with MSC-derived exosomes. Importantly, our observation of a significantly higher...
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018
driven co-expression of CXCL13 and CXCR5 is governed by a multifaceted transcriptional program re... more driven co-expression of CXCL13 and CXCR5 is governed by a multifaceted transcriptional program regulating breast cancer progression. Bbadis (2018),
We investigated expressions of -CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 b... more We investigated expressions of -CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 breast cancer (BCa) patients and correlated with transforming growth factor-β (TGF-β) expression. We observed an inverse correlation of TGF-β expression with CCL2, CCL5 expression in early stages of BCa. On contrary, in late stages, CCL2, not CCL5, expression was found to be directly proportional with TGF-β expression. TGF-β stimulated MDA-MB-231 cells to express CCL2, however, downregulated both CCL2 and CCL5 in MCF-7. Interestingly, a significant swing of Th1-Th2 ratio towards Th2 is seen within the primary tumors expressing moderate/high-CCL2-low/negative-CCL5. We observed that CCL2-CCR2 interaction induces monocytes/macrophages to secrete Th2-attracting chemokine CCL22 in vitro. Therefore, CCL2 secreted from the tumor microenvironment may attract and interact with monocytes/macrophages, and favor Th2 accumulation by inducing CCL22 secretion. Study in 4T1-BALB/c BCa mouse model demonst...
The multifunctional cytokine TGF-β crucially participates in breast cancer (BCa) metastasis and w... more The multifunctional cytokine TGF-β crucially participates in breast cancer (BCa) metastasis and works differently in the disease stages, thus contributing in BCa progression. We address connections between TGF-β and the stem cell-related transcription factor (TF) Oct4 in BCa. In 147 BCa patients with infiltrating duct carcinoma, we identified a significantly higher number of cases with both moderate/high Oct4 expression and high TGF-β in late stages compared to early stages of the disease. In vitro studies showed that TGF-β elevated Oct4 expression, which in turn, regulated Epithelial-to-Mesenchymal transition (EMT)-regulatory gene (Snail and Slug) expression, migratory ability, chemotactic invasiveness and extracellular matrix (ECM) degradation potential of BCa cells. Putative binding sites for Oct4 on the snail, slug and cxcl13 promoters and for Smad3 on the snail and slug promoters were identified. Promoter activities of snail and slug were greater in dual-treated cells than only...
Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we descri... more Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we describe a novel mechanism by which mesenchymal stem cell (MSC)-derived exosomes drive an immunosuppressive program within the breast tumor microenvironment. Initial q-PCR and immunophenotyping of human breast tumor samples, and TCGA data analysis confirmed a positive correlation between infiltrations of MSC and M2 macrophage phenotype, therefore we hypothesized that MSC promote M2 macrophage differentiation in breast tumors. We then performed a series of experiments in vitro and in vivo, and found that MSC-derived exosomes significantly promote differentiation of macrophages into PD-L1 expressing ‘M2-like’ phenotype, while also enhancing malignant progression of breast tumors, in vivo. Additionally, we observed increased invasive potential of tumor cells with higher expression of mesenchymal markers when induced with MSC-derived exosomes. Importantly, our observation of a significantly higher TGF-β production by tumor associated macrophages in exosome-induced tumors, with stronger PD-1 expression by intra-tumoral T cells, suggests TGF-β driven PD-1 upregulation. Blocking of PD-L1 abrogates exosome-induced tumor growth signifying the PD-L1/PD-1 checkpoint pathway is vital to MSC-induced tumor progression. Together, infiltration of MSCs within breast tumors drives the increased invasive potential as well as immune-checkpoint-mediated immunosuppression through inducing PD-L1 expression by tumor associated macrophages and PD-1 expression by T cells. Targeting infiltration of MSCs into the breast tumor therefore is a potential approach to reduce breast tumor metastases and improve efficacy of immunotherapies.
Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we descri... more Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we describe a novel mechanism by which mesenchymal stem cell (MSC)-derived exosomes drive an immunosuppressive program within the breast tumor microenvironment. Initial q-PCR and immunophenotyping of human breast tumor samples, and TCGA data analysis confirmed a positive correlation between infiltrations of MSC and M2 macrophage phenotype, therefore we hypothesized that MSC promote M2 macrophage differentiation in breast tumors. We then performed a series of experiments in vitro and in vivo, and found that MSC-derived exosomes significantly promote differentiation of macrophages into PD-L1 expressing ‘M2-like’ phenotype, while also enhancing malignant progression of breast tumors, in vivo. Additionally, we observed increased invasive potential of tumor cells with higher expression of mesenchymal markers when induced with MSC-derived exosomes. Importantly, our observation of a significantly higher...
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018
driven co-expression of CXCL13 and CXCR5 is governed by a multifaceted transcriptional program re... more driven co-expression of CXCL13 and CXCR5 is governed by a multifaceted transcriptional program regulating breast cancer progression. Bbadis (2018),
We investigated expressions of -CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 b... more We investigated expressions of -CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 breast cancer (BCa) patients and correlated with transforming growth factor-β (TGF-β) expression. We observed an inverse correlation of TGF-β expression with CCL2, CCL5 expression in early stages of BCa. On contrary, in late stages, CCL2, not CCL5, expression was found to be directly proportional with TGF-β expression. TGF-β stimulated MDA-MB-231 cells to express CCL2, however, downregulated both CCL2 and CCL5 in MCF-7. Interestingly, a significant swing of Th1-Th2 ratio towards Th2 is seen within the primary tumors expressing moderate/high-CCL2-low/negative-CCL5. We observed that CCL2-CCR2 interaction induces monocytes/macrophages to secrete Th2-attracting chemokine CCL22 in vitro. Therefore, CCL2 secreted from the tumor microenvironment may attract and interact with monocytes/macrophages, and favor Th2 accumulation by inducing CCL22 secretion. Study in 4T1-BALB/c BCa mouse model demonst...
The multifunctional cytokine TGF-β crucially participates in breast cancer (BCa) metastasis and w... more The multifunctional cytokine TGF-β crucially participates in breast cancer (BCa) metastasis and works differently in the disease stages, thus contributing in BCa progression. We address connections between TGF-β and the stem cell-related transcription factor (TF) Oct4 in BCa. In 147 BCa patients with infiltrating duct carcinoma, we identified a significantly higher number of cases with both moderate/high Oct4 expression and high TGF-β in late stages compared to early stages of the disease. In vitro studies showed that TGF-β elevated Oct4 expression, which in turn, regulated Epithelial-to-Mesenchymal transition (EMT)-regulatory gene (Snail and Slug) expression, migratory ability, chemotactic invasiveness and extracellular matrix (ECM) degradation potential of BCa cells. Putative binding sites for Oct4 on the snail, slug and cxcl13 promoters and for Smad3 on the snail and slug promoters were identified. Promoter activities of snail and slug were greater in dual-treated cells than only...
Uploads
Papers by Suman Purohit