A bispecific Clec9A-PD-L1 targeted type I interferon profoundly reshapes the tumor microenvironment towards an antitumor state

Author:

Van Lint Sandra,Van Parys Alexander,Van Den Eeckhout Bram,Vandamme Niels,Plaisance Stephane,Verhee Annick,Catteeuw Dominiek,Rogge Elke,De Geest Jennifer,Vanderroost Nele,Roels Jana,Saeys Yvan,Uzé Gilles,Kley Niko,Cauwels Anje,Tavernier Jan

Abstract

AbstractDespite 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.

Funder

Bijzonder Onderzoeksfonds UGent

Fonds Wetenschappelijk Onderzoek

Methusalem

European Research Council

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology,Molecular Medicine

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