The incidence and prevalence rate of chronic inflammatory disorders is on the rise in the pediatric population. Recent research indicates the crucial role of interactions between the altered intestinal microbiome and the immune system in the pathogenesis of several chronic inflammatory disorders in children, such as inflammatory bowel disease (IBD) and autoimmune diseases, such as type 1 diabetes mellitus (T1DM) and celiac disease (CeD). Here, we review recent knowledge concerning the pathogenic mechanisms underlying these disorders, and summarize the facts suggesting that the initiation and progression of IBD, T1DM, and CeD can be partially attributed to disturbances in the patterns of composition and abundance of the gut microbiota. The standard available therapies for chronic inflammatory disorders in children largely aim to treat symptoms. Although constant efforts are being made to maximize the quality of life for children in the long-term, sustained improvements are still difficult to achieve. Additional challenges are the changing physiology associated with growth and development of children, a population that is particularly susceptible to medication-related adverse effects. In this review, we explore new promising therapeutic approaches aimed at modulation of either gut microbiota or the activity of the immune system to induce a long-lasting remission of chronic inflammatory disorders. Recent preclinical studies and clinical trials have evaluated new approaches, for instance the adoptive transfer of immune cells, with genetically engineered regulatory T cells expressing antigen-specific chimeric antigen receptors. These approaches have revolutionized cancer treatments and have the potential for the protection of high-risk children from developing autoimmune diseases and effective management of inflammatory disorders. The review also focuses on the findings of studies that indicate that the responses to a variety of immunotherapies can be enhanced by strategic manipulation of gut microbiota, thus emphasizing on the importance of proper interaction between the gut microbiota and immune system for sustained health benefits and improvement of the quality of life of pediatric patients.
Introduction: Over the last two decades, very compelling clinical and experimental evidences have accelerated the use of natural killer (NK) cells’ properties for the recognition and eradication of hematologic malignancies. NK cells mediate antitumor killing responses via antibody-dependent cell-mediated cytotoxicity (ADCC). In order to accelerate and sustain NK antitumor immunity, antibodies targeting antigens expressed on the membrane surface of cancer cells are used as therapeutic interventions. Here, we investigated the antitumor benefit of the combination of the therapeutic anti-CD20 antibody, rituximab, with shortlisted membrane ionophores to overcome the resistance of B-cell lymphomas toward anti-CD20 targeted monoclonal antibodies. Methods: Flow cytometry was used to quantify cell surface protein levels and the rate of tumor cell death. Serum and PBMCs of human healthy donors were used as source of complement and natural killer cells, respectively. ADCC, complement-dependent cytotoxicity (CDC), and degranulation assays were used to assess the sensitivity of NHL cell lines and primary cancer cells upon treatment with ionophores plus rituximab. RNA-seq and qPCR were used to identify and confirm the deferentially expressed genes upon ionophores treatment. GSEA, an online resource of the Broad Institute (Boston, MA), was used to screen the differentially expressed genes and major signaling pathways. Results: Our data show that the sublethal doses of these ionophores (< 0.5uM) greatly increased surface CD20 (protein target for rituximab therapy) levels onB-cell lymphoma (Burkitt and DLBCL) cell lines. B-cell lymphoma cell death induced by rituximab, either mediated by complement or NK cell cytotoxicities, was significantly increased upon treatment with ionophores. These in vitro effects have been confirmed in xenograft model in SCID mice. While rituximab treatment alone slightly delayed tumor growth, the combination of rituximab with ionophores caused a dramatic decrease (up to 3x) of tumor size. The anticipated signaling pathways influencing NK cell activity are currently being interrogated; transcriptomic analysis combined with GSEA will allow to identify markedly altered pathways that are potentially closely involved in enhancing the sensitivity of rituximab-treated B-cell lymphoma cells. Summary: The data indicate that ionophores are promising therapeutic agents that could strongly enhance CD20 expression on the surface of target tumor cells. When combined with therapeutic anti-CD20 monoclonal antibodies, impressive high NK cell-mediated cytotoxicity is demonstrated that potentially offsets the B lymphoma resistance to R-CHOP regimen. These results also support the clinical development of these molecules as adjuvant to existing cancer immunotherapies. Support: National Science Centre (NCN, Poland), ID: 2016/23/B/NZ5/02622; Ministry of Science and Higher Education in Poland, ID: DI2014007344 and iONKO grant. Citation Format: Abdessamad Zerrouqi, Anna Torun, Nina Miazek, Zofia Pilch, Jakub Golab, Beata Pyrzynska. Natural killer immune response is promoted by the treatment of B-cell lymphoma cancer cells with membrane ionophores [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B14.
The primary hurdle in non-Hodgkin lymphoma (NHL) treatment is the resistance to the recommended R-CHOP regimen which is composed of anti-CD20-targeted immunotherapy, Rituximab or RTX, and multiple chemotherapeutic drugs: cyclophosphamide, doxorubicin, vincristine and prednisone. In many patients, the resistance is correlated to the reduced level of CD20 antigen on the surface of tumor B cells. While testing drugs that overcome this resistance, we sought of testing whether Salinomycin, a drug that preferentially act on cancer cells over healthy cells, and selectively target cancer stem cells, is able to improve the sensitivity of NHL to Rituximab. Herein, we investigated its effect on NK cell- and complement-dependent cytotoxicity on NHL cells and its mechanism of action. Methods: Antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and degranulation assays were used to assess the sensitivity of NHL cell lines and primary cancer cells upon treatment with salinomycin plus rituximab. Serum and PBMCs of human healthy donors were used as source of complement and Natural Killer cells, respectively. Flow cytometry was used to quantify cell death rate and cell surface protein levels. RNA-seq and qPCR were used to identify and confirm the differentially expressed genes upon salinomycin treatment. GSEA, an online resource of the Broad Institute MA, was used to screen the differentially expressed genes and major signaling pathways. Results and Conclusions: In addition to previously reported ability of Salinomycin to kill cancer stem cells, our data show that the sub-lethal doses of Salinomycin greatly increased surface CD20 (protein target for Rituximab therapy) on both lymphoma cell lines and primary CLL samples. Lymphoma cell death induced by rituximab and mediated by complement and NK cell cytotoxicities was significantly increased upon treatment with salinomycin. Transcriptomic analysis of cells treated with salinomycin identified a sets of differentially expressed genes (including CD20-encoding gene) and markedly activated/affected pathways that are potentially involved in enhancing the sensitivity of Rituximab-treated NHL cells. The anticipated signaling pathways influencing NK cell activity will be further examined. These data indicate that salinomycin is an interesting therapeutic agent when combined with therapeutic anti-CD20 monoclonal antibodies. This particular combination would ensure higher NK cell-mediated cytotoxicity and offset the NHL resistance to R-CHOP regimen. Aknowledgements: National Science Centre (NCN), ID: 2016/23/B/NZ5/02622; Ministry of Science and Higher Education, ID: DI2014007344. Citation Format: Abdessamad Zerrouqi, Nina Miazek-Zapala, Anna Torun, Piotr Zapala, Jakub Golab, Magdalena Winiarska, Beata Pyrzynska. Salinomycin expands the cytotoxicity of both anti-CD20 monoclonal antibodies and natural killer cells towards non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-261.
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