Graft-Versus-Tumor Activity Against Renal Cell Carcinoma in a Mouse Model of HSCT.

Abstract

Patients undergoing hematopoietic stem cell transplantation (HSCT) have demonstrated responses against several solid tumors including renal cell cancer (RCC) (Childs et al. NEJM 2000). Currently, there is no murine model available to study the role of graft-versus-tumor (GVT) activity in RCC rejection. Here we demonstrate GVT activity against the renal cell carcinoma line RENCA in a MHC class I/II disparate model of C57BL/6 into BALB/c. This line has been transduced with the luciferase gene (RENCA-TGL) that allows for bioluminescence imaging (BLI) of tumor burden. Lethally irradiated recipients of T-cell depleted marrow (TCD) recipients challenged with RENCA succumb rapidly to tumor death while addition of 0.3x10^6 donor CD8+ T cells significantly prolongs survival (median survival of 34 vs 72 days, P < 0.0001) and delays tumor progression (measured by BLI). Mortality in mice challenged with RENCA compared to RENCA-TGL is similar, demonstrating that rejection is not dependent on the immunogenicity of the transduced genes. Recipients of TCD-BM + CD8+ T cells without tumor cells survive and develop minimal graft-versus-host disease (GVHD), demonstrating that CD8+ T cells can mediate potent GVT activity without lethal GVHD activity. We used T cells from donor mice deficient in cytotoxic molecules including IFNγ, TNFα, perforin, and Fas ligand (FasL) to determine the mechanism of GVT activity and found that GVT activity against RENCA activity does not require TNFα or perforin but is dependent on IFNγ and FasL. We determined the clinical significance of our findings in a minimal residual disease model. Recipient mice were challenged with RENCA-TGL one week prior to HSCT to allow for seeding of lung micrometastases. Hosts receiving bone marrow and CD8+ T cells have significantly increased survival and delay in tumor progression compared to recipients of TCD-BM without T cells. These results demonstrate GVT activity in a model similar to the clinical presentation of patients diagnosed with RCC. In conclusion, CD8+ GVT activity against RCC is dependent on IFNγ and FasL and significantly increases host survival without lethal GVHD. Our results provide the first experimental mouse model to study strategies to enhance allogeneic HSCT in the treatment of RCC.