Gene Expression Profiling In Renal Cell Cancer (Rcc) During Tumor Vaccination With A Gene-Modified Allogeneic Cancer Vaccine: Tumor-Induced Immunosuppression And A Key Role For Nf-Kappa B

e15555 Background: Tumor-induced immunosuppression is a hallmark of cancer and a major obstacle for immunotherapies. It includes impaired T cell function, reduced antigen presentation, and diminished humoral and innate immune responses. Therefore, the gene expression profile (GEP) of peripheral blood mononuclear cells (PBMCs) is very likely to reflect the immunological state and might give insights into the underlying molecular mechanisms of immunosuppression. A previously performed phase-I trial with an allogeneic, human leucocyte antigen (HLA)-A2-matched RCC cell line transfected with interleukin-7 (IL-7) and CD80 as a vaccine in RCC patients was feasible and safe, however, clinical responses and/or significant TH1-polarized immune responses were not observed. Methods: To further elucidate why our allogeneic gene-modified RCC vaccine failed to induce TH-1-polarized immune responses, PBMCs of RCC patients (n=9) and healthy controls (n=9) were analyzed by GEP both prior and after vaccination in order to identify differences in the expression of immunologically relevant genes and cellular processes. Results: At baseline, a profound and statistically significant downregulation of gene signatures associated with antigen presentation, immune response/T cells, cytokines/chemokines, and signaling/transcription factors was observed in RCC patients as compared to healthy controls. Vaccination led to a partial reversion of preexisting immunosuppression, however, GEP did not show appropriate TH-1 polarization. Moreover, various central components and a variety of known target genes of the nuclear factor-kappa B (NF-κB) signaling pathway were significantly downregulated in RCC patients´ PBMCs, implying that suppression of this signaling cascade plays a key role for the impairment of immunological responsiveness. Conclusions: Our data implicate that the GEP of PBMCs may serve as a surrogate parameter for interactions between tumor and immune system. GEP of PBMCs appears to be a useful tool for the characterization of a) tumor-induced immunosuppression and b) systemic immunological effects of immunotherapeutics.