| The idea that a functionally intact immune system can protect against cancer development forms the basis of the long-postulated and once controversial concept of cancer immunosurveillance. A substantial body of evidence, however, now exists defining a role for immunity in extrinsic tumor suppression -- work that broadened our understanding of the tumor-immune interface and led to the cancer immunoediting hypothesis. The interferons, both type I (IFNalpha/beta) and type II IFN (IFNgamma), are critical mediators of cancer immunoediting, yet their respective roles in promoting anti-tumor immune responses remain unclear. Herein, we have examined the actions of IFNalpha/beta and IFNgamma during tumor rejection, providing evidence for distinct functions on the host as well as the tumor.;We have established that host hematopoietic cells represent important targets of IFNalpha/beta's actions, however these cytokines can have potent stimulatory effects on both innate and adaptive immune cells. Using bone marrow chimeras, we demonstrated that IFNalpha/beta sensitivity within innate immune cells, but not T or B lymphocytes, was essential for the priming of tumor-specific T cells and the generation of protective immunity. Whereas NK cells were not required for IFNalpha/beta-dependent tumor rejection, CD8alpha+ dendritic cells were critical, and the direct actions of type I IFN on CD8alpha+ DCs enhanced antigen cross-presentation.;When we instead examined the requirements for IFNgamma during tumor rejection, we observed an important function for both hematopoietic and nonhematopoietic host cell sensitivity, as well as a more prolonged duration of action. Selective reconstitution and RNAi knockdown of IFNGR1 also corroborated the importance of tumor cell responsiveness to IFNgamma, but not IFNalpha/beta.;As exogenous type I IFN has shown clinical efficacy in cancer therapy, we performed similar studies using a model of IFNa immunotherapy. We observed that local production of IFNbeta could induce either reversible tumor equilibrium (at higher doses) or elimination (at lower doses). The effects of high-dose IFNbeta were independent of adaptive immunity and required hematopoietic and nonhematopoietic IFNalpha/beta responsiveness; in contrast, tumor elimination with low-dose IFNbeta required adaptive immunity and responsiveness only in hematopoietic cells. Collectively, these studies add to our understanding of the protective functions of the interferons during anti-tumor immunity. |
