1. Inhibition of adjuvant-induced TAM receptors potentiates cancer vaccine immunogenicity and therapeutic efficacy
- Author
-
Alfonso Calvo, Jay A. Berzofsky, Pablo Sarobe, David F. Stroncek, Josune Egea, David Repáraz, Esther Redin, Belén Aparicio, Juan José Lasarte, Leyre Silva, Matthew Angel, Diana Llopiz, and Marta Ruiz
- Subjects
Male ,Cancer Research ,medicine.medical_treatment ,T cell ,Melanoma, Experimental ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Article ,Mice ,Immunogenicity, Vaccine ,Lymphocytes, Tumor-Infiltrating ,Adjuvants, Immunologic ,In vivo ,Immunity ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Animals ,Humans ,Medicine ,Imiquimod ,c-Mer Tyrosine Kinase ,business.industry ,Immunogenicity ,Prostatic Neoplasms ,Receptor Protein-Tyrosine Kinases ,Dendritic Cells ,Axl Receptor Tyrosine Kinase ,Interleukin-10 ,Up-Regulation ,Blockade ,Gene Expression Regulation, Neoplastic ,Vaccination ,Poly I-C ,Pyrimidines ,medicine.anatomical_structure ,Oncology ,Quinolines ,Cancer research ,Female ,Immunotherapy ,Cancer vaccine ,business ,Adjuvant - Abstract
Analyzing immunomodulatory elements operating during antitumor vaccination in prostate cancer patients and murine models we identified IL-10-producing DC as a subset with poorer immunogenicity and clinical efficacy. Inhibitory TAM receptors MER and AXL were upregulated on murine IL-10+ DC. Thus, we analyzed conditions inducing these molecules and the potential benefit of their blockade during vaccination. MER and AXL upregulation was more efficiently induced by a vaccine containing Imiquimod than by a poly(I:C)-containing vaccine. Interestingly, MER expression was found on monocyte-derived DC, and was dependent on IL-10. TAM blockade improved Imiquimod-induced DC activation in vitro and in vivo, resulting in increased vaccine-induced T-cell responses, which were further reinforced by concomitant IL-10 inhibition. In different tumor models, a triple therapy (including vaccination, TAM inhibition and IL-10 blockade) provided the strongest therapeutic effect, associated with enhanced T-cell immunity and enhanced CD8+ T cell tumor infiltration. Finally, MER levels in DC used for vaccination in cancer patients correlated with IL-10 expression, showing an inverse association with vaccine-induced clinical response. These results suggest that TAM receptors upregulated during vaccination may constitute an additional target in combinatorial therapeutic vaccination strategies.
- Published
- 2021
- Full Text
- View/download PDF