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Project description:Neutrophils have emerged as diverse regulators of tissue states, displaying functions in both the resolution and promotion of tissue inflammation. While neutrophils have widely been associated with tumor promotion, immune suppression, and poor patient outcome, we provide evidence to support direct tumor cytotoxic properties of neutrophils. Using various models of murine breast cancer; we establish that TLR-mediated engagement, combined with complex I inhibition, within the breast tumor microenvironment, acting either directly or indirectly on neutrophils, primes these innate immune cells to acquire direct tumor killing properties, both in vitro and in vivo, and independently of CD8+ T cell immunity. TLR engagement stimulates emergency granulopoiesis, increasing levels of neutrophils in the circulation and infiltrating into tumors without inducing the formation of a pro-metastatic niche. Mechanistically, we show that systemic administration of various TLR agonists, while increasing systemic inflammation, elevates NFB signalling in neutrophils, to contribute to their tumoricidal functions. Moreover, using bulk- and single-cell RNA sequencing, along with proteomics approaches, we show that neutrophils which are trained to acquire these anti-tumorigenic functions both enhance secretory granule production and increase expression NADPH-oxidase machinery. Concomitantly, these tumoricidal neutrophils increase production of toxic levels of reactive oxygen species, which can be overcome with myeloperoxidase inhibitors or overexpression of ROS scavengers. Taken together, we describe a new class of neutrophils that possess direct and intrinsic tumoricidal functions, which can be exploited to eradicate immune cold breast tumors which otherwise are refractory to standard immunotherapies, including immune checkpoint blockade.
2025-06-04 | PXD054085 | Pride
Project description:Neutrophils have emerged as diverse regulators of tissue states, displaying functions in both the resolution and promotion of tissue inflammation. While neutrophils have widely been associated with tumor promotion, immune suppression, and poor patient outcome, we provide evidence to support direct tumor cytotoxic properties of neutrophils. Using various models of murine breast cancer; we establish that TLR-mediated engagement, combined with complex I inhibition, within the breast tumor microenvironment, acting either directly or indirectly on neutrophils, primes these innate immune cells to acquire direct tumor killing properties, both in vitro and in vivo, and independently of CD8+ T cell immunity. TLR engagement stimulates emergency granulopoiesis, increasing levels of neutrophils in the circulation and infiltrating into tumors without inducing the formation of a pro-metastatic niche. Mechanistically, we show that systemic administration of various TLR agonists, while increasing systemic inflammation, elevates NFkB signalling in neutrophils, to contribute to their tumoricidal functions. Moreover, using bulk- and single-cell RNA sequencing, along with proteomics approaches, neutrophils that are trained to acquire these anti-tumorigenic functions, acquire enhanced secretory granule production and increased expression NADPH-oxidase machinery. Concomitantly, these tumoricidal neutrophils increase production of toxic levels of reactive oxygen species, which can be overcome with myeloperoxidase inhibitors or overexpression of ROS scavengers. Taken together, we describe a new class of neutrophils that possess direct and intrinsic tumoricidal functions, which can be exploited to eradicate immune cold breast tumors which otherwise are refractory to standard immunotherapies, including immune checkpoint blockade.
2025-06-04 | GSE272922 | GEO
Project description:Neutrophils have emerged as diverse regulators of tissue states, displaying functions in both the resolution and promotion of tissue inflammation. While neutrophils have widely been associated with tumor promotion, immune suppression, and poor patient outcome, we provide evidence to support direct tumor cytotoxic properties of neutrophils. Using various models of murine breast cancer; we establish that TLR-mediated engagement, combined with complex I inhibition, within the breast tumor microenvironment, acting either directly or indirectly on neutrophils, primes these innate immune cells to acquire direct tumor killing properties, both in vitro and in vivo, and independently of CD8+ T cell immunity. TLR engagement stimulates emergency granulopoiesis, increasing levels of neutrophils in the circulation and infiltrating into tumors without inducing the formation of a pro-metastatic niche. Mechanistically, we show that systemic administration of various TLR agonists, while increasing systemic inflammation, elevates NFkB signalling in neutrophils, to contribute to their tumoricidal functions. Moreover, using bulk- and single-cell RNA sequencing, along with proteomics approaches, neutrophils that are trained to acquire these anti-tumorigenic functions, acquire enhanced secretory granule production and increased expression NADPH-oxidase machinery. Concomitantly, these tumoricidal neutrophils increase production of toxic levels of reactive oxygen species, which can be overcome with myeloperoxidase inhibitors or overexpression of ROS scavengers. Taken together, we describe a new class of neutrophils that possess direct and intrinsic tumoricidal functions, which can be exploited to eradicate immune cold breast tumors which otherwise are refractory to standard immunotherapies, including immune checkpoint blockade.
2025-06-04 | GSE272921 | GEO
Project description:Complex I Inhibition combined with TLR Activation in the Breast Tumor Microenvironment Educates Cytotoxic Neutrophils.
| PRJNA1139246 | ENA
Project description:Complex I Inhibition combined with TLR Activation in the Breast Tumor Microenvironment Educates Cytotoxic Neutrophils [scRNA-seq]
| PRJNA1139251 | ENA
Project description:Complex I Inhibition combined with TLR Activation in the Breast Tumor Microenvironment Educates Cytotoxic Neutrophils [bulk RNA-seq]
| PRJNA1139250 | ENA
Project description:Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by reducing the hyper-permeability of tumor vessels or restoring compressed vessels. Despite progress in strategies to normalize the tumor microenvironment (TME), their combinatorial antitumor effects with nanomedicine and immunotherapy remain unexplored. Methods: Here, we re-purposed the TGF-β inhibitor tranilast, an approved anti-fibrotic and antihistamine drug, and combined it with Doxil nanomedicine to normalize the TME, increase perfusion and oxygenation, and enhance anti-tumor immunity. Specifically, we employed two triple-negative breast cancer (TNBC) mouse models to primarily evaluate the therapeutic and normalization effects of tranilast combined with doxorubicin and Doxil. We demonstrated the optimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of TME normalization to the efficacy of immune checkpoint inhibitors. Results: Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrix components and an increase in the intratumoral vessel diameter and pericyte coverage, indicators of TME normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size. Tranilast further normalized the immune TME by restoring the infiltration of T cells and increasing the fraction of T cells that migrate away from immunosuppressive cancer-associated fibroblasts. Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved immunostimulatory M1 macrophage content in the tumorigenic tissue and improved the efficacy of the immune checkpoint blocking antibodies anti-PD-1/anti-CTLA-4. Conclusion: Combinatorial treatment of tranilast with Doxil optimizes TME normalization, improves immunostimulation and enhances the efficacy of immunotherapy.
| S-EPMC6993226 | biostudies-literature
Project description:The efficacy of the combination of a PARP inhibitor (PARPi) and an EZH2 inhibitor has been investigated in breast cancer cells with either BRCA1 mutation or BRCA2 mutation. However, earlier studies focused on the efficacy of this combination against BRCA-mutated but not BRCA-proficient breast cancer. Yang et al. observed that PARP1 depletion combined with EZH2 depletion via PRC2 depletion did not affect the growth of BRCA1/2 wild-type breast cancer cells in vitro. Moreover, Yang et al. reported that this combination stimulated synthetic viability of BRCA1/2-proficient breast cancer cells in vivo by regulating the tumor microenvironment to induce angiogenesis and differentiation of M2-type macrophages. The findings of Yang et al. provided evidence that both in vitro and animal models should be employed in the studies of PARPi combination therapies in order to involve the alteration of the tumor microenvironment in these investigations. These studies of PARP inhibition combined with EZH2 inhibition in breast cancer showed that this combination may benefit breast cancer patients carrying BRCA1-mutated tumor, but the combination may also enhance recurrence of BRCA2-mutated tumor and may even promote BRCA-proficient cancer cell survival. Therefore, BRCA1 mutation status should be used to select breast cancer patients for PARPi and EZH2 inhibitor combination treatment in clinical trials in the future.
| S-EPMC8096666 | biostudies-literature
Project description:Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.
| S-EPMC5917603 | biostudies-literature
Project description:An impaired neutrophil response to pathogenic fungi puts patients at risk for fungal infections with a high risk of morbidity and mortality. Acquired neutrophil dysfunction in the setting of iatrogenic immune modulators can include the inhibition of critical kinases such as spleen tyrosine kinase (Syk). In this study, we used an established system of conditionally immortalized mouse neutrophil progenitors to investigate the ability to augment Syk-deficient neutrophil function against Candida albicans with TLR agonist signaling. LPS, a known immunomodulatory molecule derived from Gram-negative bacteria, was capable of rescuing effector functions of Syk-deficient neutrophils, which are known to have poor fungicidal activity against Candida species. LPS priming of Syk-deficient mouse neutrophils demonstrates partial rescue of fungicidal activity, including phagocytosis, degranulation, and neutrophil swarming, but not reactive oxygen species production against C. albicans, in part due to c-Fos activation. Similarly, LPS priming of human neutrophils rescues fungicidal activity in the presence of pharmacologic inhibition of Syk and Bruton's tyrosine kinase (Btk), both critical kinases in the innate immune response to fungi. In vivo, neutropenic mice were reconstituted with wild-type or Syk-deficient neutrophils and challenged i.p. with C. albicans. In this model, LPS improved wild-type neutrophil homing to the fungal challenge, although Syk-deficient neutrophils did not persist in vivo, speaking to its crucial role on in vivo persistence. Taken together, we identify TLR signaling as an alternate activation pathway capable of partially restoring neutrophil effector function against Candida in a Syk-independent manner.
| S-EPMC8976732 | biostudies-literature