Regulation of Migration into Tumor Metastases

A striking difference between clustered melanoma metastases was the presence or absence of a lymphocyte gene expression signature. It is critical to perform confirmatory assays to determine whether this difference is truly reflected at the level of T cell involvement. In this case, differential presence of CD8+ T cells was confirmed by immunohistochemistry. In some instances, T cells were extremely abundant and were uniformly distributed throughout the tumor mass. This result suggests that some tumors have the capability to recruit T cells and others do not. One might imagine that even if a patient developed circulating tumor antigen-specific T cells as measured in the blood, if homing into tumor sites did not occur then tumor regression would be unlikely to follow. Another implication of this result is, assuming a subset of these T cells is antigen specific as we and others have observed in similar cases previously [9-11], then it seems likely that the tumor microenvironment has rendered the T cells dysfunctional.

Fig. 4.1 Chemokines found differentially expressed in melanoma metastases that contain or lack CD8+ T cells. This list was extracted from gene expression profiling data as being statistically different between the three tumor categories. Group 1 contained T cell-specific transcripts indicating the presence of T cells in the tumor specimen.

-CCL2, CCL3, CCL4, CCL5, CCL19, CCL21 - CXCL9, CXCL10, CXCL11, CXCL13 -CXCL8, CXCL12

It was of interest to understand in more detail the possible mechanism for differential migration of T cells into melanoma metastases. Correlating with the presence of T cells was expression of a broad array of chemokine genes (Fig. 4.1). These data were confirmed by real-time RT-PCR and for a subset of them by protein array on tumor lysates. Based on the chemokine receptors upregulated on CD8+ effector T cells and known chemokine-receptor interactions, the list of candidate chemokines was narrowed to 6 (MIP-1a, MIP-1P, MCP-1, Mig, IP-10, and RANTES). Each of these chemokines was found to be sufficient for recruiting CD8+ effector T cells in a transwell system in vitro. Thus, it seems likely that a cooperative activity of these 6 chemokines helps to support recruitment of activated CD8+ T cells into tumor sites in vivo. Absence of these chemokines might therefore represent a barrier that precludes T cell recruitment and implies that inadequate T cell migration may be defined as an immune evasion mechanism.

Previous studies of primary melanoma lesions support a chemokine correlation with T cell infiltrates. It is well known that primary cutaneous melanomas sometimes have a brisk T cell infiltrate yet in other cases show a complete absence of T cells. Immunohistochemical staining has shown an association of T cell infiltration with expression of the chemokines Mig/CXCL9 and IP-10/CXCL10 [12]. Interestingly, these factors appeared to be produced by monocyte/macrophage-like cells in the tumor microenvironment, suggesting that the phenotype of this stromal cell component might help dictate the nature of the inflammatory infiltrate in melanoma tumors.

Mouse models have been utilized to explore whether introduction of chemokines into the tumor microenvironment may improve T cell migration in vivo. Expression of CCL2/MCP-1, CCL3/MIP-1a, CCL5/RANTES, CCL21/SLC, and CXCL10/IP-10 by tumor cells have each been found to improve antitumor immunity in various mouse tumor models [13, 14]. An interesting alternative to consider is the TNF super-family member LIGHT. In binding to the LTpR, LIGHT triggers expression of a broad range of chemokines from stromal cells, including CCL21 and CCL3, and drives generation of a secondary lymphoid-like structure [15]. In tumor models, expression of LIGHT has been shown to promote recruitment of both naïve and activated CD8+ T cells and support vigorous tumor rejection in vivo [16]. For clinical translation, use of a viral vector to transfer expression of LIGHT in tumor sites following direct injection might be considered. Preclinical experiments using an adeno-viral vector encoding murine LIGHT have shown promising results, yielding not only increased T cell recruitment in the injected tumor but also control of micrometastatic disease (Yu et al, J Immunol., In Press). Thus, use of LIGHT to modify the tumor microenvironment is attractive to consider for clinical translation.

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