Understanding the mechanism by which CD4 + T cells sensitize mesenchymal CD73-deficient tumors to anti-CTLA4 immune checkpoint blockade therapy

Triple-Negative Breast Cancer (TNBC) is a highly aggressive disease with poor patient outcomes due to its resistance to chemotherapy and immunotherapy. Despite its efficacy in Melanoma and Lung carcinoma, immune checkpoint blockade (ICB) therapy is only effective in a small minority of TNBC patients. Epithelial-to-Mesenchymal Transition (EMT) is a key driver of malignant progression leading to greater metastatic potential and an immunosuppressive tumor microenvironment, driving resistance to therapies. Our previous results demonstrate that epithelial tumors respond to anti-CTLA4 therapy while mesenchymal tumors are resistant. Strikingly, knockout of CD73 in mesenchymal tumors results in complete sensitization to anti-CTLA4 treatment but not anti-PD1 therapy, the more clinically used treatment. Using our preclinical mouse models together with immunofluorescence staining, we observed that CD73-deficient tumors display increased infiltration of CD4 + and CD8 + T cells upon anti-CTLA4 treatment relative to non-responding controls. Most notably, while CD73 deficient tumors continued to respond to anti-CTLA4 treatment without CD8 + T cells, they failed to respond in the absence of CD4 + T cells. However, the mechanisms by which CD4 + T cells facilitate the elimination of mesenchymal tumors remain unknown. Preliminary results demonstrate that cytotoxic CD4 + T cells play a crucial role in potentiating the response of CD73-deficient tumors to anti-CTLA4. Moreover, tumors contain plastic CD4 + T cell subsets that reduce immune suppression under anti-CTLA4 treatment while promoting immune suppression under anti-PD1 treatment. These results reveal that CD4 + T cells can specifically target lethal mesenchymal cancer cells in response to anti-CTLA4 but not anti-PD1 therapy. Future work is aimed at understanding whether CD4 + T cells eliminate tumors via direct interactions with cancer cells or through indirect activation of other immune cells. Given the inefficacy of anti-PD1 therapy in TNBC clinical trials, characterizing the CD4 + T cell response to anti-CTLA4 provides a mechanistic basis for leveraging its therapeutic potential.