Denileukin diftitox reduces EL4 lymphoma growth by depleting regulatory T cells, which can be improved by αICOS (VAC12P.1116)

Immunotherapy shows promise in carcinoma treatments. As less is known about effects on lymphomas, we tested EL4 T cell lymphoma. We found that EL4 cells were CD25 - CTLA4 - B7H1 lo PD1 hi by flow cytometry. Immune checkpoint blockade with αCTLA4, αB7H1, or αPD1 antibodies had no effect on tumor growth in EL4-challenged mice. αCD25 worked as prophylaxis (before EL4 challenge) but not therapy, despite depleting regulatory T cells (Tregs). In Foxp3 DTR mice, specific Treg depletion reduced EL4 tumor growth, suggesting Treg depletion as a good treatment strategy. Denileukin diftitox (DD) is a relatively-specific Treg depletion drug with clinical benefits in mouse and human cancer. DD (5 μg/4 days starting 4 days after EL4 challenge) significantly delayed EL4 tumor growth and increased survival (P=.002) in WT mice. DD protection was lost in βδ TCR KO mice lacking all T cells, suggesting a T cell dependent treatment mechanism. In EL4-challenged WT, DD depleted Tregs > αCD25 but significantly increased ICOS by 2-fold on remaining Tregs > than on CD4 + or CD8 + T cells in tumor draining lymph nodes. Nearly all Tregs within tumors were ICOS + . ICOS + Tregs were mostly CD44 + with hi Ki-67, suggesting activation that reduced DD treatment effects. In support, αICOS (100 μg/4 days starting 1 day after DD) enhanced DD-mediated EL4 tumor growth inhibition, but did not improve overall survival. DD-mediated Treg depletion plus αICOS and/or other adjuncts could lead to effective lymphoma immunotherapy.