RT Journal Article
SR Electronic
T1 Tumor rejection in <em>Cblb</em><sup>−/−</sup> mice depends on IL-9 and Th9 cells
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e002889
DO 10.1136/jitc-2021-002889
VO 9
IS 7
A1 Oliver Schanz
A1 Isabelle Cornez
A1 Sowmya Parampalli Yajnanarayana
A1 Friederike Sophie David
A1 Sebastian Peer
A1 Thomas Gruber
A1 Peter Krawitz
A1 Peter Brossart
A1 Annkristin Heine
A1 Jenny Landsberg
A1 Gottfried Baier
A1 Dominik Wolf
YR 2021
UL http://jitc.bmj.com/content/9/7/e002889.abstract
AB Background Casitas B lymphoma-b (Cbl-b) is a central negative regulator of cytotoxic T and natural killer (NK) cells and functions as an intracellular checkpoint in cancer. In particular, Th9 cells support mast cell activation, promote dendritic cell recruitment, enhance the cytolytic function of cytotoxic T lymphocytes and NK cells, and directly kill tumor cells, thereby contributing to tumor immunity. However, the role of Cbl-b in the differentiation and antitumor function of Th9 cells is not sufficiently resolved.Methods Using Cblb−/− mice, we investigated the effect of knocking out Cblb on the differentiation process and function of different T helper cell subsets, focusing on regulatory T cell (Treg) and Th9 cells. We applied single-cell RNA (scRNA) sequencing of in vitro differentiated Th9 cells to understand how Cbl-b shapes the transcriptome and regulates the differentiation and function of Th9 cells. We transferred tumor-model antigen-specific Cblb−/− Th9 cells into melanoma-bearing mice and assessed tumor control in vivo. In addition, we blocked interleukin (IL)-9 in melanoma cell-exposed Cblb−/− mice to investigate the role of IL-9 in tumor immunity.Results Here, we provide experimental evidence that Cbl-b acts as a rheostat favoring Tregs at the expense of Th9 cell differentiation. Cblb−/− Th9 cells exert superior antitumor activity leading to improved melanoma control in vivo. Accordingly, blocking IL-9 in melanoma cell-exposed Cblb−/− mice reversed their tumor rejection phenotype. Furthermore, scRNA sequencing of in vitro differentiated Th9 cells from naïve T cells isolated from wildtype and Cblb−/− animals revealed a transcriptomic basis for increased Th9 cell differentiation.Conclusion We established IL-9 and Th9 cells as key antitumor executers in Cblb−/− animals. This knowledge may be helpful for the future improvement of adoptive T cell therapies in cancer.Data are available in a public, open access repository. Data are available upon reasonable request.