Journal Article

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

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

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: AcTakine / Antigens / Antitumor activity / B7-H1 Antigen / B7-H1 Antigen - metabolism / Biological response modifiers / Biomedical and Life Sciences / Biomedicine / Body temperature / Cancer / Cancer immunotherapy / Cancer Research / Cancer therapies / CD8 antigen / CD8-Positive T-Lymphocytes / Cdc2 protein / Cell Line, Tumor / Chemotherapy / Cytokines / Cytotoxicity / Development and progression / Effector cells / Humans / Immune checkpoint / Immune clearance / Immune response / Immune system / Immunity / Immunogenicity / Immunological memory / Immunology / Immunotherapy / Inflammation / Interferon / Interferon Type I / Interferon Type I - metabolism / Leukocytes (neutrophilic) / Life Sciences / Ligands / Lymphocytes / Lymphocytes T / Macrophages / Melanoma / Metastases / Metastasis / Natural killer cells / Neoplasms / Neoplasms - metabolism / Oncology / PD-L1 protein / T cells / Tumor Microenvironment / Tumors / Type I Interferon