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The mRNA profiles of the macrophages with or without Trastuzumab-dependent tumor phagocytosis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119342 | GEO | 2018/09/04

REPOSITORIES: GEO

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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.

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.

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The mRNA profiles of the macrophages with or without Trastuzumab-dependent tumor phagocytosis

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