Targeting Tr1 Cells to Enhance Cancer Immunotherapy

Dr. Sultan’s research focuses on understanding and overcoming the immune suppressive mechanisms that limit the efficacy of cancer immunotherapies, particularly cancer vaccines. Many cancer immunotherapies rely on T cells, which can distinguish healthy cells from cancerous cells by tumor specific antigens. Vaccines build on this efficacy by generating or amplifying tumor specific IT-cell responses with great specificity. However, so far, vaccines do not live up to their promise because they can be countered by immune suppression. Dr. Sultan’s previous work found that the suppression of cancer vaccines is not just the work of conventional suppressive T cells but is likely linked to a more specialized type 1 regulatory IT cell (TrI cells) that can actively suppress anti–tumor immunity and might actually be induced by poorly designed vaccines.

Dr. Sultan has identified EBI3, a gene critical in inducing immune response, as strongly implicated in cancer progression and he hypotheses that EBI3 promotes Tr1 differentiation and contributes to immunotherapy resistance. Notably, antibody-[HS1.1]mediated blockade of EBI3 markedly reduces Trl cell frequency and restores effective IT cell-mediated tumor control. With his Young Investigator Award, Dr. Sultan will employ a new physiological system to define how EBI3 regulates tumor immunity and whether its direct inhibition will change the composition of the tumor microenvironment. He will also analyze banked blood and tumor samples from leukemia patients to define Trl associated gene programs and immunosuppressive mechanisms in human samples, establishing the gene signature and phenotypic identity of human Trl cells. Through this project, Dr. Sultan hopes to establish a direct connection linking EBI3 signaling to Tr1 mediated immunosuppression and develop strategies to block EBI3 to enhance antitumor immunity and to design better immunotherapeutic vaccines and other therapies.