Rapamycin directly inhibits T cell lymphoma proliferation at high doses and facilitates immune-independent toxin-mediated killing at a low dose in vivo.

Abstract

Abstract Hyperactive mammalian target of rapamycin (mTOR) signaling that drives tumor growth makes mTOR inhibition an attractive cancer therapeutic strategy. mTOR inhibitors are approved to treat certain carcinomas, but effects on T cell hematologic malignancies, which also express hyper-activated mTOR, are less reported. We studied effects of the mTOR inhibitor rapamycin (Rapa) in mouse EL4 T cell lymphoma. Typical pharmacologic Rapa doses (1–8 mg/kg) significantly reduced tumor burden and improved survival in subcutaneous EL4 challenge independent of interferon (IFN)-γ or host T cells which we showed was by direct suppression of tumor cell proliferation. Though we found EL4 refractory to many anti-cancer immunotherapies, its growth was significantly slowed by regulatory T cell depletion with denileukin diftitox (DD) in vivo in a T cell-dependent fashion. However, typical Rapa doses inhibited T cell activation and tumor infiltration in vivo and failed to boost DD treatment effects as expected. Low dose (LD, 75 μg/kg) Rapa reportedly improves anti-tumor immunity and we found it increased potentially beneficial CD8+ T cells with a central memory phenotype (CD44hiCD62L+) in EL4 challenge, but without clinical effect. LD Rapa significantly enhanced DD treatment efficacy, but surprisingly, DD + LD Rapa treatment effects were independent of T cells, IFN-γ or perforin. Instead, Rapa up-regulated EL4 IL-2 receptor expression (DD binding site) in vitro and in vivo, apparently facilitating direct DD tumor cell killing. We thus show an unexpected mechanism for mTOR inhibitor in cancer immunotherapy and show distinct, biphasic mechanisms of action at typical pharmacologic doses versus LD Rapa that can be exploited clinically.