Host type I IFN signals mediate awareness of tumor and promote spontaneous adaptive immune responses against tumor-associated antigens through CD8á+ dendritic cells

MERCEDES BEATRIZ FUERTES; JUSTIN KLINE; AALOK KACHA; THOMAS GAJEWSKI

Keystone, Colorado, Estados Unidos

Simposio; Keystone Symposium Role of Inflammation in Oncogenesis (J5); 2010

Keystone Symposia

Contrary to preconceptions, spontaneous T cell priming against tumor antigens occurs frequently in response to a growing tumor both in murine and in human systems.  Gene expression profiling of human melanoma metastases revealed the presence of an interferon (IFN) signature in T cell-containing tumors.  Mechanistic experiments were performed in murine models to determine a causal role of host type I IFNs as an innate bridge to T cell priming.  Following subcutaneous implantation of B16 melanoma cells in B6 mice, IFN-b was induced in the tumor draining lymph nodes within 3-5 days, which preceded detection of a tumor antigen-specific CD8+ T cell response.  In Stat1 ko mice defective in IFN-based signaling or in type I IFNR ko mice, T cell priming and tumor rejection were nearly abrogated.  Bone marrow chimera experiments revealed a requirement for IFN signaling in the hematopoietic compartment for spontaneous rejection of immunogenic tumors in vivo.  Adoptive transfer experiments with WT TCR transgenic T cells, or immunization with WT antigen-pulsed dendritic cells (DCs), pointed to a type I IFN-dependent effect at the level of host antigen presenting cells. Analysis of DC subsets from mice defective in IFN-based signaling revealed no apparent deficiency in terms of numbers, B7-1/B7-2 expression, or CD40 expression. In vivo, processing and presentation of tumor antigen as measured by TCR tetramer staining of tumor-infiltrating DCs was intact, as was migration of DCs to LNs as measured by FITC painting of skin.  To probe potential mechanisms further, bone marrow-derived DCs (BMDCs) from wildtype and Stat1-deficient mice were studied in vitro.  Stat1-/- DCs showed a 50% decrease in IL-12 p70 secretion and a severe reduction in the expression of the costimulatory molecule CD70 after stimulation through TLR 7/8, an effect which depends on an autocrine type I IFN loop.  Gene expression profiling in response to exogenous type I IFNs revealed up-regulated expression of several chemokine transcripts, including IP-10, MCP-1, MIG, and MIP-1â.  The potent induction of these chemokines was confirmed using a cytokine bead array.  In vivo, endogenous type I IFNs were required for intratumoral accumulation of CD8a+ DCs.  Our results indicate that IFN-b induction is a critical component of the innate immune recognition of a growing tumor and identify a link between type I IFN activity and activation of a subset of DC functions, which could explain the critical role of this pathway in spontaneous cross-priming of tumor antigen-specific CD8+ T cells in vivo.  Rational manipulation of the type I IFN system could lead to improved anti-tumor immunity in vivo by augmenting spontaneous adaptive immune responses.