Anti-CD4 treatment increases tumor-suppressive IL18Rαhi CD8+ T cells

Anti-CD4 monoclonal antibody, a prominent immunomodulatory agent, elicits robust anti-tumor immunity in various cancers by increasing tumor-infiltrating lymphocytes and promoting CD8+ T cell reactivity against tumor cell-derived antigens. We conducted single-cell transcriptome analysis of anti-CD4-exposed lymphoid cells to investigate the detailed mechanism. The model of mouse melanoma (B16F10) was used to study anti-CD4-induced change of lymphoid cells. We designed a regimen that utilizes cyclophosphamide treatment, adoptive transfer of tumor-specific T cells, and anti-CD4 treatment, a combination that synergistically increases the efficacy of adoptive T cell therapy. Three days after the B16F10 challenge, C57BL/6 mice sequentially received cyclophosphamide, ex vivo-primed Pmel-1 cells (melanoma-specific TCR-transgenic CD8+ T cells), and IL-2. A transient treatment (on day 10, 17, and 24) of anti-CD4 started seven days after cyclophosphamide treatment. Twenty-five days after the tumor challenge, cells from lymphoid tissues of the mice were subjected to single-cell transcriptome analysis. Two groups (3 mice each) received cyclophosphamide/Pmel-1 or cyclophosphamide/Pmel-1/anti-CD4. For each group, endogenous CD8+ T cells from three mice were pooled and used in the analysis.