Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16INK4a and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo.
Keywords: CIP1, CDK-interacting protein 1; DNAM-1, DNAX accessory molecule-1; KIR, killer-cell immunoglobulin-like receptor; M1/M2 macrophages; MICA/B, MHC class I polypeptide-related sequence A/B; NKG, natural killer group; NSG, NOD SCID gamma chain knock out mouse; PCNA, proliferating cell nuclear antigen; PVR, poliovirus receptor; RMS, rhabdomyosarcoma, (eRMS: embryonal, aRMS: alveolar); ROI, region of interest; RORC, RAR-related orphan receptor C; SCT, stem cell transplantation; SPECT/CT, single-photon emission computed tomography; TH1-induced senescence; TH17 cells; TRBV, T-cell receptor beta chain; ULBP, UL16 binding protein; WAF, wild-type activating fragment; cancer-targeted IL-12; differentiation; humanized mice; immunocytokine; immunotherapy; pHP1γ, phosphorylated heterochromatin protein 1 gamma; rhabdomyosarcoma; tumor-infiltrating lymphocytes.