Control of B-cell lymphoma by therapeutic vaccination and acquisition of immune resistance is independent of direct tumour IFN-gamma signalling

Immunomodulatory therapies can effectively control haematological malignancies by promoting antitumour immunity. Previously, we reported transient growth of poorly immunogenic murine non-Hodgkin B-cell lymphomas (B-NHL) by targeting natural killer T (NKT) cells with a therapeutic vaccine approach. Therapeutic efficacy was highly dependent on the ability of the vaccine to provoke rapid interferon-gamma (IFN gamma) production from NKT and NK cells. By manipulating the capacity of either host or lymphoma cells to signal through the IFN gamma receptor (IFN gamma R), we investigated whether the therapeutic effect conferred by vaccine-induced IFN gamma is a result of immune cell activation, lymphoma IFN gamma sensitivity or a combination of both. We demonstrated that antitumour immunity elicited by vaccination requires IFN gamma signalling within host cells but not tumour cells. IFN gamma R-deficient mice failed to mount an effective antitumour immune response following vaccination despite elevated IFN gamma levels. With successive exposure to vaccination, lymphomas acquired an increasingly therapy-resistant phenotype and displayed a reduction in major histocompatibility complex I and CD1d surface expression, which is independent of tumour intrinsic IFN gamma signalling. Our results suggest that immunotherapy-induced IFN gamma production mainly exerts its therapeutic effect via signalling through host cells, rather than directly to tumour cells in B-NHL. This signifies that intact IFN gamma signalling within patients' immune compartment rather than tumour cell sensitivity to IFN gamma is more critical for successful treatment. Finally, tumour IFN gamma signalling alone does not drive acquired tumour resistance to vaccination, implying that additional immunoediting pathways are responsible for tumour immune escape.