Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE233484 | GEO | 2024/07/08
REPOSITORIES: GEO
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Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted. Comparison of trastuzumab (n=4) and TDM-1 (n=4) treated BT-474 human breast carcinoma cells growing in murine brain
2015-11-09 | E-GEOD-69042 | biostudies-arrayexpress
Project description:Tumor-infiltrating (TI)-NK cell numbers predict better than TIL score the efficacy of HER2-targeted antibodies in primary breast cancer patients. To understand the mechanism/s underlying this association, biological processes enriched in NK cell-infiltrated as compared to NK cell-desert HER2-positive breast tumors paired by TIL score were leveraged from transcriptomic data. NK cell-infiltrated tumors were enriched in transcripts regulated by interferons and NF-kB. Among them, levels of CCL5/IFNG-CXCL9/10 positively correlated with the number of TI-NK cells in the original biopsy. Indeed, coordinated expression of CCL5/IFNG-CXCL9/10 transcripts was also evidenced in tumor biopsies from a phase II clinical trial where IFNG levels associated to the achievement of pathological complete response to anti-HER2 antibody treatment (OR 96.3, p=0.01) and correlated with their TI-NK cell score. In in vitro models, anti-HER2 antibody-dependent NK cell activation led to the secretion of CCL5/IFN-? and the subsequent production of IFN-?-dependent CXCL9/10 by bystander breast cancer cells. Ex vivo treatment of breast tumor-derived multicellular cultures with trastuzumab induced the activation of CD16+ TI-NK cells and their conversion into a CD16-CD103+ subpopulation, both endowed with CCL5 and IFN-? producing potential. CD16+ and CD16-CD103+ TI-NK cell subpopulations shared the expression of EOMES, TBX21 and several KIR genes, indicating their lineage relationship; and their proportions positively correlated with total NK cell, CD8+ and tissue-resident T cell frequencies, immune cell subsets with anti-tumor potential. Remarkably, the coordinated induction of CCL5/IFNG-CXCL9/CXCL10 expression, concomitant to the conversion of CD16+ into CD16+/-CD103+ tumor-infiltrating NK cells, was recapitulated in a humanized HER2+ breast cancer in vivo model treated with a combination of anti-HER2 antibodies and in vitro expanded human NK cells, paralleling tumor growth control. Finally, patients achieving good clinical responses to anti-HER2 antibody-based neoadjuvant treatment showed an early and coordinated increase in sera CCL5 and CXCL9/CXCL10 levels which positively correlated with TI-NK cell numbers in the corresponding diagnosis biopsy. Overall, our data point to NK cells as regulators of the tumor microenvironment through the early secretion of CCL5/IFN-? resulting in the production of CXCL9/10 and the recruitment/differentiation of immune infiltrates with anti-tumor potential, ultimately contributing to anti-HER2 antibody clinical efficacy.
2024-01-10 | GSE230536 | GEO
Project description:Tumor-infiltrating (TI)-NK cell numbers predict better than TIL score the efficacy of HER2-targeted antibodies in primary breast cancer patients. To understand the mechanism/s underlying this association, biological processes enriched in NK cell-infiltrated as compared to NK cell-desert HER2-positive breast tumors paired by TIL score were leveraged from transcriptomic data. NK cell-infiltrated tumors were enriched in transcripts regulated by interferons and NF-kB. Among them, levels of CCL5/IFNG-CXCL9/10 positively correlated with the number of TI-NK cells in the original biopsy. Indeed, coordinated expression of CCL5/IFNG-CXCL9/10 transcripts was also evidenced in tumor biopsies from a phase II clinical trial where IFNG levels associated to the achievement of pathological complete response to anti-HER2 antibody treatment (OR 96.3, p=0.01) and correlated with their TI-NK cell score. In in vitro models, anti-HER2 antibody-dependent NK cell activation led to the secretion of CCL5/IFN-ɣ and the subsequent production of IFN-ɣ-dependent CXCL9/10 by bystander breast cancer cells. Ex vivo treatment of breast tumor-derived multicellular cultures with trastuzumab induced the activation of CD16+ TI-NK cells and their conversion into a CD16-CD103+ subpopulation, both endowed with CCL5 and IFN-ɣ producing potential. CD16+ and CD16-CD103+ TI-NK cell subpopulations shared the expression of EOMES, TBX21 and several KIR genes, indicating their lineage relationship; and their proportions positively correlated with total NK cell, CD8+ and tissue-resident T cell frequencies, immune cell subsets with anti-tumor potential. Remarkably, the coordinated induction of CCL5/IFNG-CXCL9/CXCL10 expression, concomitant to the conversion of CD16+ into CD16+/-CD103+ tumor-infiltrating NK cells, was recapitulated in a humanized HER2+ breast cancer in vivo model treated with a combination of anti-HER2 antibodies and in vitro expanded human NK cells, paralleling tumor growth control. Finally, patients achieving good clinical responses to anti-HER2 antibody-based neoadjuvant treatment showed an early and coordinated increase in sera CCL5 and CXCL9/CXCL10 levels which positively correlated with TI-NK cell numbers in the corresponding diagnosis biopsy. Overall, our data point to NK cells as regulators of the tumor microenvironment through the early secretion of CCL5/IFN-ɣ resulting in the production of CXCL9/10 and the recruitment/differentiation of immune infiltrates with anti-tumor potential, ultimately contributing to anti-HER2 antibody clinical efficacy.
2024-01-10 | GSE230521 | GEO
Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted.
2015-11-09 | GSE69042 | GEO
Project description:ACE1702 (anti-HER2 oNK cells) is an off-the-shelf Natural Killer (NK) cell product that targets human HER2-expressing solid tumors. The ACE1702-001 phase I study aims to evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ACE1702 in patients with advanced or metastatic HER2-expressing tumors, and to determine the phase Ib/II starting dose for ACE1702.
| 2333964 | ecrin-mdr-crc
Project description:Therapeutic antibodies trigger antibody-dependent cellular cytotoxicity (ADCC) of cancer cells and also their antibody-dependent cellular phagocytosis (ADCP) by tumor-associated macrophages (TAMs). We report here our unexpected finding that TAMs that have undergone ADCP of tumor cells induced by therapeutic antibodies display immunosuppressive characteristics and inhibit the proliferation and tumoricidal effects of NK and tumor-specific CD8+ T cells in breast cancers and lymphomas. Mechanistically, we show that DNA released from the phagocytosed tumor cells after ADCP activates caspase 1 inflammasome, leading to IL-1β-mediated PD-L1 and IDO upregulation in these cells. Combined treatment with anti- HER2 antibody and inhibitors of PD-L1 and IDO increased the infiltration of NK and CD8+ T cells and enhanced anti- HER2 therapeutic efficacy in mouse models of HER2+ breast cancers. Furthermore, neo-adjuvant Trastuzumab therapy significantly increased PD-L1 and IDO expression in the TAMs of HER2+ breast cancer patients, which correlate with poor Trastuzumab response and reduced NK and CD8+ T cells in the tumors. Collectively, our findings unveil an unexpected role of ADCP induced by therapeutic antibodies in cancer immunosuppression, and suggest that antibody plus immune checkpoint blockade may provide synergistic therapeutic effects in cancer patients.
2018-09-04 | GSE119342 | GEO
Project description:Rheumatoid arthritis (RA) is linked to depression and dementia in later life by inflammatory involvement of the central nervous system (CNS). Regional heterogeneity of brain immunophenotypes was described under homeostasis, but a topographical resolution of CNS immune responses in chronic peripheral inflammatory diseases like RA is missing. We demonstrate regional heterogeneity of CNS susceptibility to chronic peripheral inflammation in the human tumor necrosis factor α transgenic (TNFtg) mouse model of RA. TNFtg mice showed myeloid cell infiltration, microglial activation, and a mutual transcriptomic fingerprint of neuroinflammation in the cortex, striatum, and thalamus. Immune responses were minimal in the hippocampus and cerebellum. We demonstrate regional CNS immune responses to chronic peripheral inflammation, sparing the hippocampus and cerebellum and reversible by peripheral anti-inflammatory treatment. Targeting microenvironmental susceptibility or resilience of brain regions will help to prevent and treat RA-related neuropsychiatric comorbidity. RNA-sequencing was performed from five brain regions (cortex, striatum, thalamus, hippocampus, and cerebellum) from C57Bl6/J wild type mice and TNFtg mice (strain Tg197; kindly provided by George Kollias (Fleming Institute, Vari, Greece).
2018-10-22 | E-MTAB-7279 | biostudies-arrayexpress
Project description:We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we developed clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduced tumor burden, prolonged survival, remodeled the TME, increased intratumoral T cell and natural killer (NK) cell infiltration, and induced epitope spreading. CAR-M therapy protected against antigen-negative relapse in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors resistant to anti-PD1(aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improved tumor growth control, survival, and remodeling of the TME. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to enhance response to aPD1 therapy for patients with non-responsive tumors.
2024-12-22 | GSE285188 | GEO
Project description:We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we developed clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduced tumor burden, prolonged survival, remodeled the TME, increased intratumoral T cell and natural killer (NK) cell infiltration, and induced epitope spreading. CAR-M therapy protected against antigen-negative relapse in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors resistant to anti-PD1(aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improved tumor growth control, survival, and remodeling of the TME. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to enhance response to aPD1 therapy for patients with non-responsive tumors.
2024-11-20 | GSE275417 | GEO
Project description:Purpose: There is an unmet clinical need for biomarkers to identify breast cancer patients who are at increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with HER2+ brain metastasis. Experimental Design: Gene expression of 19 HER2+ breast cancer brain metastases was compared with HER2+ nonmetastatic primary tumors. Gene Set Enrichment Analysis was used to identify a signature, which was evaluated for correlation with BRCA1 mutation status and clinical outcome using published microarray datasets and for correlation with pharmacological inhibition by a PARP inhibitor and temozolomide using published microarray datasets of breast cancer cell lines. Results: A BRCA1 Deficient-Like (BD-L) gene signature is significantly correlated with HER2+ metastases in both our and an independent cohort. BD-L signature is enriched in BRCA1 mutation carrier primary tumors and HER2-/ER- sporadic tumors, but high values are found in a subset of ER+ and HER2+ tumors. Elevated BD-L signature in primary tumors is associated with increased risk of overall relapse, brain relapse, and decreased survival. The BD-L signature correlates with pharmacologic response to PARP inhibitor and temozolomide in two independent microarray datasets, and the signature outperformed four published gene signatures of BRCA1/2 deficiency. Conclusions: The BD-L signature is enriched in breast cancer brain metastases and identifies a subset of primary tumors with increased propensity for brain metastasis. Furthermore, this signature may serve as a biomarker to identify sporadic breast cancer patients who could benefit from a therapeutic combination of PARP inhibitor and temozolomide. Gene expression of 19 HER2+ human breast cancer brain metastases was compared with gene expression of 19 HER2+ nonmetastatic primary human breast tumors.
2014-04-24 | E-GEOD-43837 | biostudies-arrayexpress