Human CD4+ effector memory T cells persisting in the tumor microenvironment of non-small cell lung cancer: Evaluation of mechanisms responsible for tissue retention and activation in the context of an IL-12-induced anti-tumor response
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The chronic inflammatory state associated with non-small cell lung cancer, and its functional significance and capabilities, have remained somewhat of an enigma: tumors progress and spread in the presence of tumor-specific B and T cells. The hypothesis is put forth that the dynamic microenvironment of most human, primary non-small cell lung tumors contains memory T cells that are unresponsive to T cell receptor triggering while maintaining the ability to be re-activated by the administration of exogenous IL-12 to eradicate tumor cells in situ by indirect mechanisms that are dependent upon IFN-γ. Using a human/SCID mouse chimeric model characterized by the subcutaneous implantation of intact pieces of human cell lung cancer biopsy tissue, it is possible to study the early cellular events that occur within the human tumor microenvironment in response to IL-12, namely the activation and expansion of CD3+ T cells which produce measurable levels of IFN-γ leading to tumor cell eradication. The majority CD3+ T cell population was found to display an activated (CD45RO+) phenotype consistent with that of a CD4+ effector memory T cell, i.e. positive for CD3, CD4, CD45RO, CXCR3+, CD28+, CD44+ and CD11a+, and IL-12 receptor (β1 subunit) and is negative for CD27, CD45RA, and CD62L. The mechanisms responsible for the prolonged persistence of these T cells in the microenvironment over the course of tumor development have not yet been established. However, it was recently shown that type I interferons inhibit the apoptosis of CD4+ T cells in the periphery. Data presented here using immunohistochemistry and flow cytometry have identified plasmacytoid dendritic cells capable of producing IFN-α which may contribute to CD4+ memory T cell retention in the tumor. Upon isolation from the tumor microenvironment, the memory T cells were found to be unresponsive to activation via the T cell antigen receptor, as determined by the lack of translocation of NF-κB or NFAT from the cytoplasm into the nucleus, in response to CD3+CD28 cross-linking under conditions which maximally translocated these proteins in peripheral blood T cells from a normal donor or from cancer patients. The ability of the tumor-associated T cells to completely translocate NF-κB in response to TNF-α indicated that these cells remain receptive to alternative signaling pathways. Furthermore, the non-responsiveness to TCR cross-linking could be reversed by first pulsing these T cells with IL-12. The data suggests that memory T cells may be suppressed/regulated by mechanisms present in chronic inflammatory microenvironments. TGF-β is one candidate for mediating this inflammatory regulation since elution of the memory cells and subsequent treatment with TGF-β could reverse and re-instate the repressed state, respectively. Successful manipulation of the tumor microenvironment has important implications for immunotherapy against solid tumors in that it may be possible to reduce tumor bulk, if not completely eradicate the tumor, by locally activating specific anti-tumor cells. The re-activation of T cells in the tumor microenvironment and death of tumor cells may lead to tumor antigen release and the development of a systemic anti-tumor response.