Immune-mediated cancer regression requires tumor infiltration by Ag-specific effector T cells, but lymphocytes are commonly sparse in melanoma metastases. Activated T cells express CXCR3, whose cognate chemokines are CXCL9/MIG, CXCL10/IP-10 and CXCL11/I-TAC. Little is known about expression of these chemokines in lymph node (LN) metastases of melanoma. We evaluated whether metastatic melanoma induces these CXCR3-cognate chemokines in human LNderived tissues. Also, because these chemokines can be induced by interferon (IFN), we evaluated whether type I or II IFNs (IFN-α or IFN-γ, respectively) can modulate chemokine expression in an in vitro model of the human tumor microenvironment. Production of CXCL9-11 by melanomainfiltrated nodes (MIN) was no different than tumor-free nodes (TFN); both produced less chemokine than activated LN (sentinel immunized nodes, SIN). These data suggest melanoma infiltration into LN neither induces nor reduces CXCL9-11. Stimulation with IFN-α or IFN-γ increased production of CXCL10-11 from MIN, but not TFN or SIN. IFN-γ also increased production of CXCL9 in MIN. In IFN-treated SIN, CD14 + cells were the primary source of CXCL9-11, whereas melanoma cells were the source of chemokine in MIN. Melanoma cells in MIN express IFN receptors. Consistent with these observations, multiple human melanoma lines expressed IFN receptors and produced CXCL9-11 in response to IFN treatment. Thus, melanoma infiltration of LN is insufficient to induce the production of CXCL9-11, but melanoma may be a significant source of IFN-induced chemokines. Collectively, these data suggest that IFN-α or IFN-γ may act in the tumor microenvironment to increase the chemotactic gradient for CXCR3 + T cells.

To combat the ever-changing pool of pathogens we face, B cells generate highly optimized antibodies in two distinct steps. A large variety of antibodies are first generated randomly by V(D)J recombination, and then, upon encountering an antigen, antibodies are fine-tuned by somatic hypermutation and class switch recombination--both of which are initiated by the same protein, activation-induced cytidine deaminase (AID). All three processes are highly mutagenic, and mistargeting of each of these has been shown to contribute to tumorigenesis. We study these processes because they provide an excellent model to understand how highly mutagenic reactions are channeled into productive use by cells and the consequent risk this carries. In this review, we will discuss many of the outstanding questions in the field that we grapple with while developing a consistent model for AID action. We will also discuss the complexity added to these models by the recent finding that AID might be part of a demethylase complex.