HSV-1-sensitive B16F10 melanoma tumors experienced long-term (>100-day) viability and stability without clearance or outgrowth when continually treated i.t. with an IL-12-expressing HSV-1 vector. Treatment induced an IFNγ response and Th1-type CD4+ T cells. Loss of IFNγ (through mAb blockade or in IFNγ-/- mice), but not depletion of T or NK cells, tumor β2m or caspase 8, or host perforin perturbed this equilibrium, which was achieved through redundant mechanisms. IFNγR1 knockout in all three of tumor cells, hematopoietic host cells, and non-hematopoietic host cells was required for tumor escape.
Contributed by Alex Najibi
ABSTRACT: Tumors in immune equilibrium are held in balance between outgrowth and destruction by the immune system. The equilibrium phase defines the duration of clinical remission and stable disease, and escape from equilibrium remains a major clinical problem. Using a non-replicating HSV-1 vector expressing interleukin-12 (d106S-IL12), we developed a mouse model of therapy-induced immune equilibrium, a phenomenon previously seen only in humans. This immune equilibrium was centrally reliant on interferon-γ (IFNγ). CD8+ T cell direct recognition of MHC class I, perforin/granzyme-mediated cytotoxicity, and extrinsic death receptor signaling such as Fas/FasL were all individually dispensable for equilibrium. IFNγ was critically important and played redundant roles in host and tumor cells such that IFNγ sensing in either compartment was sufficient for immune equilibrium. We propose that these redundant mechanisms of action are integrated by IFNγ to protect from oncogenic or chronic viral threats and establish IFNγ as a central node in therapy-induced immune equilibrium.