Modulation des Tumor-Mikromilieus durch CAR NK-Zellen
Zusammenfassung der Projektergebnisse
Natural killer (NK) cells play a critical role in antitumor immunity by directly eliminating malignant cells and by regulating tumor-specific adaptive immune responses. NK-cell-based cancer immunotherapies are typically based on adoptive transfer of donor-derived allogeneic NK cells. To enhance their antitumor activity, NK cells can be further engineered to express chimeric antigen receptors (CARs) that facilitate selective recognition and killing of tumor cells, with early stage clinical development of several such approaches ongoing. Nevertheless, in addition to pro-inflammatory cytokines such as IFN-γ, activated NK and CAR-NK cells secrete high levels of immunoregulatory IL-10, which can counteract proinflammatory factors and dampen tumor-suppressive activities of bystander immune cells in the tumor microenvironment. Utilizing a novel approach based on intracellular expression of an IL-10 blocking antibody, in the framework of this project we evaluated the consequences of IL-10 depletion on the interaction of clinically used NK-92/5.28.z CAR-NK cells with bystander immune cells in in vitro co-culture systems. Thereby, enhanced dendritic cell maturation and prevention of M2-like macrophage polarization were found upon exposure to the modified CAR-NK cells. These two myeloid cell types are most crucial for overcoming an immunosuppressive tumor microenvironment and the induction of adaptive antitumor immunity. In separate approaches, we also investigated ectopic expression of an IL-15 superagonist (RD-IL15) or a PD-L1-targeted IL-15 immunocytokine in CAR-NK cells. Both strategies resulted in autocrine stimulation of the CAR-NK cells and independence from exogenous IL-2. The secreted molecules also activated co-cultured innate lymphocytes and T cells, enhancing growth and antitumoral activity of such bystander immune cells. In an immunocompetent mouse glioblastoma model, treatment with IL-10 depleted NK- 92/5.28.z/anti-IL10ER and immunocytokine-secreting NK-92/5.28.z/anti-PDL1-RD-IL15 cells in comparison to unmodified NK-92/5.28.z markedly enhanced infiltration of the tumors by endogenous immune cells and further delayed tumor growth. Thereby, the observed differences in the infiltrating mouse immune cell subsets were consistent with the findings in in vitro co-culture assays with human immune cells. Taken together, our results demonstrate a marked enhancement of the immunomodulatory activity of CAR-NK cells depleted of IL-10 or expressing the IL-15 superagonist. Thereby, the added benefit of blockade of IL-10 was likely due to a reduction of immunosuppressive cell types such as M2-like macrophages and Treg cells, while the anti-PDL1-RD-IL15 immunocytokine enhanced the activity of innate lymphocytes and T cells more directly. In addition to the direct antitumor activity of CAR- engineered lymphocytes, their potential to reshape the tumor microenvironment and enhance endogenous antitumor immunity is likely crucial to overcome the currently very limited efficacy of CAR approaches in solid tumor indications. Hence, our findings may be highly relevant for the improvement of CAR-NK therapeutics as well as other engineered cell types employed for adoptive cancer immunotherapy.
Projektbezogene Publikationen (Auswahl)
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Bispecific antibody-mediated redirection of NKG2D-CAR natural killer cells facilitates dual targeting and enhances antitumor activity. Journal for ImmunoTherapy of Cancer, 9(10), e002980.
Zhang, Congcong; Röder, Jasmin; Scherer, Anne; Bodden, Malena; Pfeifer, Serrahima Jordi; Bhatti, Anita; Waldmann, Anja; Müller, Nina; Oberoi, Pranav & Wels, Winfried S.
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Co-Expression of an IL-15 Superagonist Facilitates Self-Enrichment of GD2-Targeted CAR-NK Cells and Mediates Potent Cell Killing in the Absence of IL-2. Cancers, 15(17), 4310.
Bodden, Malena; Häcker, Aline; Röder, Jasmin; Kiefer, Anne; Zhang, Congcong; Bhatti, Anita; Pfeifer, Serrahima Jordi; Ullrich, Evelyn; Kühnel, Ines & Wels, Winfried S.
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Multivalent adaptor proteins specifically target NK cells carrying a universal chimeric antigen receptor to ErbB2 (HER2)-expressing cancers. Cancer Immunology, Immunotherapy, 72(9), 2905-2918.
Pfeifer, Serrahima Jordi; Zhang, Congcong; Oberoi, Pranav; Bodden, Malena; Röder, Jasmin; Arndt, Claudia; Feldmann, Anja; Kiefer, Anne; Prüfer, Maren; Kühnel, Ines; Tonn, Torsten; Bachmann, Michael & Wels, Winfried S.
