Doxorubicin enhances CD4⁺ T-cell immune responses by inducing expression of CD40 ligand and 4-1BB

Chemotherapy agents have adverse immunotherapeutic effects secondary to inhibition of hematopoietic stem cell proliferation, particularly in committed lymphoblast. Certain anti-cancer drugs have immuno-modulatory properties, although mechanisms are still not fully understood. In the current study, we explored the effects of doxorubicin on peripheral blood CD4⁺ and CD8⁺ T-cell responses pre- and post-stimulation. Doxorubicin treatment alone had no effects on peripheral blood T lymphocytes and regulatory T-cells in vivo and in vitro. However, CD4⁺ T-cells were resistant to doxorubicin and demonstrated more robust proliferation than CD8⁺ T-cells after doxorubicin pre-treatment. CD40 ligand and 4-1BB expression on the surface of CD4⁺ T-cells were increased after TCR-ligation activation; however, expression on CD8⁺ T-cells was not increased. Dendritic cells cultured in the presence of activated CD4⁺ T-cells pre-treated with doxorubicin had greater survival rates than those cultured with activated CD8⁺ T-cells. Doxorubicin pre-treatment followed by anti-CD3ε + anti-4-1BB activation led to proliferation of CD4⁺ T-cells and no proliferative effects on CD8⁺ T-cells. Our results collectively suggest that doxorubicin pre-treatment in cancer patients may be a more effective way to enhance anti-cancer immune responses by increased antigen-specific CD4⁺ Th1 immune responses.