The development of an effective anti-tumor immune response is compromised in patients with renal cell carcinoma (RCC). Tumor infiltrating lymphocytes (TIL) have been characterized as functionally impaired and displaying poor induction of the transcription factor, NFKB. Tumor-induced apoptosis may be a contributing factor to this immunosuppression, as in situ TUNEL assays from our laboratory indicate that 15 percent of the CD3+ cells within the tumor bed are apoptotic. The notion that RCC may also be mediating a systemic effect on T cells is suggested by the observation that peripheral blood T cells from 60 percent of these patients are defective in NFKB activation. Recent studies also demonstrated that peripheral blood T cells from 40 percent of RCC patients are highly susceptible to activation-induced cell death (AICD). We hypothesize that impaired NFKB activation and increased sensitivity of T cells apoptosis contribute to the immune dysfunction in RCC patients which results in tumor progression and poor clinical outcome. The experiments proposed here will take advantage of the large RCC patient population at the Cleveland Clinic Foundation.
Aim1 will determine whether the NFKB activation defect and susceptibility to AICD are related phenomena in patient T cells. This will include testing of a correlation exists between AICD susceptibility and impaired NFKB activation and whether purified T cell subsets expressing one defect also express the other. Other experiments will determine whether this linkage is in fact mediated by depressed expression of the NFKB -dependent anti-apoptotic gene products in AICD susceptible cells, and whether AICD resistance, like the NFKB activation, returns to normal when defective RCC T cells are cultured in vitro. The involvement of the well characterized Fas and TNFR pathways in RCC T cell AICD susceptibility will additionally be assessed, as the pro-apoptotic ligands for these receptors are known to be inducible in an NFKB-independent fashion.
Aim 2 will correlate the molecular findings obtained for patients in Aim 1 to several clinical correlates of immune function. Specifically, the proposed experiments will determine whether the defect in NFKB activity and sensitivity to AICD correlate with impaired DTH responsiveness and decreased survival in patients with metastatic RCC. This assessment will also involve an analysis of select anti-apoptotic genes. These studies should assess whether the defect in NFkappaB and AICD sensitivity are linked and relate to patient outcome.
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| Chahlavi, Ali; Rayman, Patricia; Richmond, Amy L et al. (2005) Glioblastomas induce T-lymphocyte death by two distinct pathways involving gangliosides and CD70. Cancer Res 65:5428-38 |
| Thornton, Mark V; Kudo, Daisuke; Rayman, Patricia et al. (2004) Degradation of NF-kappa B in T cells by gangliosides expressed on renal cell carcinomas. J Immunol 172:3480-90 |
