CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

Abstract

Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α–primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15−/− and IL-7−/− recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2+ CD8 T cells with autologous dendritic cells loaded with MART126–35 peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.

Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment

“…Indeed, we have recently demonstrated that loss of IFNAR1 stimulates growth of transplanted melanomas (Katlinskaya et al, 2016). Overall, our data are consistent with intra-tumoral IFN production being linked with CTL generation and viability (Hiroishi et al, 2000), observations that IFN may act to improve the effect of adoptive transfer of CTL (Hervas-Stubbs et al, 2012) and with recent finding that a specific CAR design, which serendipitously increased IFN signaling in CTL, evoked an augmented therapeutic effect (Zhao et al, 2015). Nevertheless, our results do not rule out additional putative cellular targets (e.g.…”

Type I Interferons as Stimulators of DC-Mediated Cross-Priming: Impact on Anti-Tumor Response

“…Furthermore, intratumoral delivery of IFN-I synergized with immunotherapy (79) and chemotherapy (47) to induce therapeutic response in tumor-bearing mice that involved, in both cases, enhanced DC cross-presentation. Notably, IFN-I can enhance anti-tumor CTL responses also via direct effects on CD8 T cells, inducing their expansion and acquisition of effector functions thus improving therapeutic efficacy (80, 81). …”

Antitumor Immunotherapeutic and Toxic Properties of an HDL-Conjugated Chimeric IL-15 Fusion Protein

“…CTLL-2 is a stable subclone of cytotoxic T lymphocytes originally isolated from a C57BL/6 mouse and 200 U/mL of IL-2 (Preprotech) was added in its culture medium (16). Peripheral blood mononuclear cell (PBMC) were obtained from filters of blood donation units under informed consent following approval of the Institutional Ethical Committee, carboxyfluorescein succinimidyl ester (CFSE) stained and monitored as described (17). Details on the isolation of mononuclear cells from spleen, lung, and liver, as well as antibodies, flow cytometry, and immunoshistochemistry can be found in Supplementary Methods.…”