Van Lint et al. showed that tumor-bearing mice treated with a mutated IFN-α2 coupled to bispecific single-domain antibodies targeting both PD-L1 and cDC1-expressed Clec9A (bispecific AcTaferon, bisp-AFN) effectively and safely induced antitumor activity, dependent on IFN signaling in immune cells and tumor cell PD-L1. Bisp-AFN combined with non-curative doxorubicin had curative effects, and induced abscopal responses and memory. Bisp-AFN increased TME levels of proinflammatory TAMs, neutrophils, and inflammatory cDC2s; matured migratory cDC1s, NK cells, NKT cells and tumor-specific CTLs; decreased regulatory T cell levels; and induced TCR epitope spreading.
Contributed by Paula Hochman
ABSTRACT: Despite major improvements in immunotherapeutic strategies, the immunosuppressive tumor microenvironment remains a major obstacle for the induction of efficient antitumor responses. In this study, we show that local delivery of a bispecific Clec9A-PD-L1 targeted type I interferon (AcTaferon, AFN) overcomes this hurdle by reshaping the tumor immune landscape.Treatment with the bispecific AFN resulted in the presence of pro-immunogenic tumor-associated macrophages and neutrophils, increased motility and maturation profile of cDC1 and presence of inflammatory cDC2. Moreover, we report empowered diversity in the CD8(+) T cell repertoire and induction of a shift from naive, dysfunctional CD8(+) T cells towards effector, plastic cytotoxic T lymphocytes together with increased presence of NK and NKT cells as well as decreased regulatory T cell levels. These dynamic changes were associated with potent antitumor activity. Tumor clearance and immunological memory, therapeutic immunity on large established tumors and blunted tumor growth at distant sites were obtained upon co-administration of a non-curative dose of chemotherapy.Overall, this study illuminates further application of type I interferon as a safe and efficient way to reshape the suppressive tumor microenvironment and induce potent antitumor immunity; features which are of major importance in overcoming the development of metastases and tumor cell resistance to immune attack. The strategy described here has potential for application across to a broad range of cancer types.
Author Info: (1) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent (CRIG), Ghent, Belgium. (2) Cente
Author Info: (1) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent (CRIG), Ghent, Belgium. (2) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent (CRIG), Ghent, Belgium. Present Affiliation: Orionis Biosciences, Ghent, Belgium. (3) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent (CRIG), Ghent, Belgium. (4) Cancer Research Institute Ghent (CRIG), Ghent, Belgium. VIB Single Cell Core, VIB, Ghent-Leuven, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (5) VIB Nucleomics Core, Leuven, Belgium. (6) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (7) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (8) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Present Affiliation: Orionis Biosciences, Ghent, Belgium. (9) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Present Affiliation: Orionis Biosciences, Ghent, Belgium. (10) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. (11) VIB Single Cell Core, VIB, Ghent-Leuven, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. (12) Data Mining and Modelling for Biomedicine, VIB & Center for inflammation research, Ghent University, Ghent, Belgium. Department of Applied Mathematics, Computer Science and Statistics, Faculty of Science, Ghent University, Ghent, Belgium. (13) IRMB, University Montpellier, INSERM, CNRS, Montpellier, France. (14) Orionis Biosciences, Ghent, Belgium. Orionis Biosciences, Boston, USA. (15) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. Present Affiliation: Orionis Biosciences, Ghent, Belgium. (16) Center for Medical Biotechnology, VIB & Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. jan.tavernier@vib-ugent.be. Cancer Research Institute Ghent (CRIG), Ghent, Belgium. jan.tavernier@vib-ugent.be. Orionis Biosciences, Ghent, Belgium. jan.tavernier@vib-ugent.be. Orionis Biosciences, Boston, USA. jan.tavernier@vib-ugent.be.
