Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rγ^null Mice

Non-disrupted pieces of primary human lung tumor implanted into NOD-scid IL2Rγ^null mice consistently result in successful xenografts in which tissue architecture, including tumor-associated leukocytes, stromal fibroblasts, and tumor cells are preserved for prolonged periods with limited host-vs-graft interference. Human CD45⁺ tumor-associated leukocytes within the xenograft are predominantly CD3⁺ T cells with fewer CD138⁺ plasma cells. The effector memory T cells that had been shown to be quiescent in human lung tumor microenvironments can be activated in situ as determined by the production of human IFN-γ in response to exogenous IL-12. Plasma cells remain functional as evidenced by production of human Ig. Significant levels of human IFN-γ and Ig were detected in sera from xenograft-bearing mice for up to 9 wk postengraftment. Tumor-associated T cells were found to migrate from the microenvironment of the xenograft to the lung, liver, and primarily the spleen. At 8 wk postengraftment, a significant portion of cells isolated from the mouse spleens were found to be human CD45⁺ cells. The majority of CD45⁺ cells were CD3⁺ and expressed a phenotype consistent with an effector memory T cell, consisting of CD4⁺ or CD8⁺ T cells that were CD45RO⁺, CD44⁺, CD62L^-, and CD25^-. Following adoptive transfer into non-tumor bearing NOD-scid IL2Rγ^null mice, these human T cells were found to expand in the spleen, produce IFN-γ, and maintain an effector memory phenotype. We conclude that the NOD-scid IL2Rγ^null tumor xenograft model provides an opportunity to study tumor and tumor-stromal cell interactions in situ for prolonged periods.