Human CD4 T cells coordinate antitumor immunity through indirect antigen presentation

Whether human tumor-specific CD4 T cells can drive antitumor immunity in cancers lacking tumor-cell MHC class II expression has not been established. In MHC class II-negative melanoma and breast cancer, CD4 T cells with a transcriptional signature of tumor specificity correlated with myeloid and CD8 T cell activation. Using a patient-derived NY-ESO-specific, HLA-DP04-restricted TCR, we tested whether human CD4 T cells could control tumors through indirect antigen presentation. In vitro, CD4 T cells inhibited HLA-DP-negative melanoma growth through recognition of tumor-derived antigen on antigen presenting cells (APC). In humanized mice, CD4 T cell transfer induced regression of HLA-DP-negative tumors, and control required HLA-matched human APCs. CD4 T cell transfer induced endogenous CD8 T cell proliferation and myeloid activation that mirrored immune programs correlated with the presence of these cells in patients. These findings establish that human tumor-specific CD4 T cells coordinate antitumor immunity through APC without direct tumor recognition, supporting their therapeutic relevance in MHC class II-negative cancers.

Roy, G., Ruterbusch, M., Bakhtiari, J., Shasha, C., Lee, S. M., Moshiri, A. S., Wood, C., Hopwo, K., Witkowski, M., Szeto, J., Singhi, N., Iuliano, M., Guenette, S., McKenna, K. M., Newell, E., Rongvaux, A., Veatch, J. R.

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