E3 Ubiquitin Ligase Cbl-b deficient T cells resist Treg cell-mediated suppression and enhance anti-tumor immunity

Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we specifically investigated the role of E3 ubiquitin ligase Cbl-b in establishing T cell resistance to Treg cell-mediated suppression. First, we found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered CD8+ T cells impartial to Treg cell-mediated suppression. Transcriptomic analyses suggest that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-γ by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. We recapitulated our findings in a syngeneic murine model by first confirming that adoptively transferred tumor specific CD8+ T cells are susceptible to regulation by Treg cells. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-γ blockade. Next we examined the effect of Cbl-b deficiency in CD4+ T cell compartment. Ablation of Cbl-b rendered CD4+ T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b deficient CD4+ T cells hyper-produced IL-2 and together with IL-2Rα upregulation served as an essential mechanism to escape suppression by Treg cells. In summary, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of cytokines as a key mechanism which renders T cells resistant to Treg cell-mediated suppression. Such a strategy could be potentially incorporated in adoptive T cell therapy to generate robust effector T cell responses and anti-tumor immunity.

Department dc:contributor.department

Immunology

Year dc:date.issued

2021

Author dc:creator

• Han, Seong Jun

Advisor dc:contributor.advisor

• Ohashi, Pamela S

• Cancer immunology
• Immuno-oncology
• Immunotherapy
• Regulatory T cell
• T cell

Handle dc:identifier.uri

http://hdl.handle.net/1807/125911

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/125911