Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA555825 | ENA |
REPOSITORIES: ENA
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Project description:Re-education of immune cells in tumor microenvironment is required for optimal treatment outcome. The prevailing notion is that B cells, a major immune cell type in tumors, are immunosuppressive and pro-tumoral. However, why B cells inhibit tumor progression in certain contexts remains unexplained. By single cell dissection of B cell heterogeneity in longitudinal samples of breast cancer patients before and after neoadjuvant chemotherapy, we revealed a distinct subset of B cells emerges after chemotherapy, which is predictive for therapeutic efficacy and prognosis in multiple patient cohorts. Using three immunocompetent mouse models, our in vivo experiments faithfully recapitulated the subset switch of human tumor-infiltrating B cells during chemotherapy. Employing B-specific deletion and adoptive transfer experiment, we showed that ICOSL in this B cell subset boosts anti-tumor immunity by enhancing the ratio of effector and regulatory T cells. The signature of ICOSL+ B cell subset is imprinted by complement-CR2 signaling, which is triggered by chemotherapy-induced immunogenic tumor cell death. Moreover, by screening the cell line encyclopedia, we identified CD55, a complement inhibitory protein, determines the dual roles of B cells in the response of various malignancies to chemotherapy. Collectively, our study demonstrates a critical role of B cell subset switch in chemotherapy response and have implications for designing novel therapeutic approaches.
2020-03-13 | GSE135710 | GEO
Project description:Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with chemotherapy following resection of a triple-negative breast tumor induced the expression of complement factors in lung fibroblasts and modulated an immunosuppressive metastatic niche that supported lung metastasis. CAF-derived complement signaling mediated the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Functionally, we show that pharmacological targeting of complement signaling in combination with chemotherapy alleviated immune dysregulation and attenuated lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.
2022-09-01 | GSE208289 | GEO
Project description:Mortality from breast cancer is almost exclusively a result of tumor metastasis and resistance to therapy and therefore understanding the underlying mechanisms is an urgent challenge. Chemotherapy, routinely used to treat breast cancer, induces extensive tissue damage, eliciting an inflammatory response that may hinder efficacy and promote metastatic relapse. Here we show that systemic treatment with doxorubicin, but not cisplatin, following resection of a triple-negative breast tumor induced the expression of complement factors in lung fibroblasts and modulated an immunosuppressive metastatic niche that supported lung metastasis. CAF-derived complement signaling mediated the recruitment of myeloid-derived suppressor cells (MDSCs) to the metastatic niche, thus promoting T cell dysfunction. Pharmacological targeting of complement signaling in combination with chemotherapy alleviated immune dysregulation and attenuated lung metastasis. Our findings suggest that combining cytotoxic treatment with blockade of complement signaling in triple-negative breast cancer patients may attenuate the adverse effects of chemotherapy, thus offering a promising approach for clinical use.
2022-09-12 | GSE207990 | GEO
Project description:Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer
| PRJNA857914 | ENA
Project description:A minimally parameterized mathematical model for low-dose metronomic
chemotherapy is formulated that takes into account angiogenic signaling between
the tumor and its vasculature and tumor inhibiting effects of tumor-immune system
interactions. The dynamical equations combine a model for tumor development under
angiogenic signaling formulated by Hahnfeldt et al. with a model for tumor-immune
system interactions by Stepanova. The dynamical properties of the model are analyzed.
Depending on the parameter values, the system encompasses a variety of medically
realistic scenarios that range from cases when (i) low-dose metronomic chemotherapy
is able to eradicate the tumor (all trajectories converge to a tumor-free equilibrium
point) to situations when (ii) tumor dormancy is induced (a unique, globally asymp-
totically stable benign equilibrium point exists) to (iii) multi-stable situations that have
both persistent benign and malignant behaviors separated by the stable manifold of
an unstable equilibrium point and finally to (iv) situations when tumor growth can-
not be overcome by low-dose metronomic chemotherapy. The model forms a basis
for a more general study of chemotherapy when the main components of a tumor’s
microenvironment are taken into account
2020-02-03 | MODEL2002030001 | BioModels
Project description:Conventional chemotherapy achieves clinical efficacy beyond its cytotoxic effects by reactivating immune surveillance. However, whether chemotherapy promotes immune evasion by remodeling the tumor microenvironment (TME) remains largely unexplored. Here, we integrate cross-species single-cell and spatial transcriptomics to explore how chemotherapy reprograms immune cell dynamics and plasticity. Our findings reveal a central role for chemotherapy-educated, liver-resident Kupffer cells (KCs) in promoting immune tolerance and chemoresistance in liver metastases. These reprogrammed KCs, characterized by leptin receptor expression (LEPR+), originate from preexisting KCs and are differentiated via STING-ID1 signaling triggered by cGAMP released from chemotherapy-treated tumor cells. Unlike conventional KCs, LEPR+ KCs infiltrate tumors and engage in MerTK-dependent efferocytosis, which diminishes chemotherapy-induced immunogenic cell death (ICD) and suppresses antitumor immunity. Notably, targeting LEPR+ KCs enhances tumor immunogenicity and strengthens antitumor T-cell responses. Our study demonstrates that therapy-induced KC differentiation fosters immune evasion and suggests combining efferocytosis inhibitors with immunotherapy to overcome chemoresistance.
2025-12-29 | GSE285990 | GEO
Project description:Conventional chemotherapy achieves clinical efficacy beyond its cytotoxic effects by reactivating immune surveillance. However, whether chemotherapy promotes immune evasion by remodeling the tumor microenvironment (TME) remains largely unexplored. Here, we integrate cross-species single-cell and spatial transcriptomics to explore how chemotherapy reprograms immune cell dynamics and plasticity. Our findings reveal a central role for chemotherapy-educated, liver-resident Kupffer cells (KCs) in promoting immune tolerance and chemoresistance in liver metastases. These reprogrammed KCs, characterized by leptin receptor expression (LEPR+), originate from preexisting KCs and are differentiated via STING-ID1 signaling triggered by cGAMP released from chemotherapy-treated tumor cells. Unlike conventional KCs, LEPR+ KCs infiltrate tumors and engage in MerTK-dependent efferocytosis, which diminishes chemotherapy-induced immunogenic cell death (ICD) and suppresses antitumor immunity. Notably, targeting LEPR+ KCs enhances tumor immunogenicity and strengthens antitumor T-cell responses. Our study demonstrates that therapy-induced KC differentiation fosters immune evasion and suggests combining efferocytosis inhibitors with immunotherapy to overcome chemoresistance.
2025-12-29 | GSE285989 | GEO
Project description:Resistance to chimeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms including antigen-loss escape and tumor-induced immune suppression. Expression of multiple CARs may overcome multi-antigen-loss escape. Similarly, expression of switch receptors that convert inhibitory immune checkpoint signals into positive costimulatory signals may enhance CAR T cell activity in the tumor microenvironment. Engineering multiple features into one cell product, however, is limited by transgene packaging constraints of current vector systems. Here, we describe a leucine zipper-based cell sorting methodology that enables selective single-step immunomagnetic purification of cells co-transduced with two vectors, designed to potentially double the number of incorporated transgenes. This “Zip-sorting” system facilitated generation of T cells simultaneously expressing up to four CARs and co-expressing up to three switch receptors. These multi-CAR multi-Switch receptor arrays enabled T cells to eliminate antigenically heterogeneous syngeneic leukemia populations co-expressing multiple inhibitory ligands. Zip-sorted multi-CAR multi-Switch receptor T cells represent a combinatorial therapeutic strategy to overcome multiple mechanisms of CAR T cell resistance.
2024-11-24 | GSE253563 | GEO
Project description:Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer [RNA-seq]
| PRJNA859133 | ENA
Project description:Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations and play a critical role in the dynamics of the tumor microenvironment. Previously, the extracellular signals of CAFs have been attributed to extracellular matrix, cytokine, cell-surface checkpoints and exosome. Here, we showed that CD10, which is a transmembrane hydrolase expressed on a subset of CAFs, supports tumor stemness and induced chemoresistance. Mechanistically, CD10 degenerates an anti-tumoral peptide, osteogenic growth peptide (OGP). OGP restrains the expression of a rate-limiting desaturase and inhibits lipid desaturation which is required for cancer stem cells (CSCs). Therapeutically, targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10-OGP signals are associated with the response of neo-adjuvant chemotherapy in patients of breast cancer. Overall, our data suggested that a nexus between the niche and lipid metabolism in CSCs can be a promising therapeutic target for breast cancer.
2021-10-19 | GSE156470 | GEO