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Fas Ligand Expression in Metastatic Renal Cell Carcinoma During Interleukin-2 Based Immunotherapy

No In vivo Effect of Fas Ligand Tumor Counterattack

Departments of ¹ Oncology, ² Pathology, and ³ Radiology, Aarhus University Hospital, Aarhus, Denmark; and ⁴ Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark

Purpose: It has been hypothesized that tumor cells expressing Fas ligand (FasL) might be able to counterattack and neutralize tumor-infiltrating lymphocytes. We assessed the effect of FasL tumor counterattack on the clinical outcome of interleukin-2 (IL-2)–based immunotherapy in metastatic renal cell carcinoma.

Experimental Design: Tumor core needle biopsies were obtained before IL-2–based immunotherapy in 86 patients and repeated within the first cycle in 57 patients. Tumor cells expressing FasL and intratumoral lymphocyte subsets expressing CD4, CD8, CD56, and CD57 were analyzed by immunohistochemistry.

Results: At baseline, negative FasL staining in tumor cells was seen in 10 of 86 (12%) biopsies, whereas intense FasL staining was seen (a) in fewer than 10% of tumor cells in 26 (30%) biopsies; (b) in 11 to 50% of tumor cells in 25 (29%) biopsies; (c) in 51 to 90% of tumor cells in 18 (21%) biopsies; and (d) in >90% of tumor cells in 7 (8%) biopsies. On treatment, tumor FasL expression did not change from baseline levels. Moreover, tumor FasL expression was not correlated with objective response or survival whereas the absolute number of CD4⁺, CD8⁺, CD56⁺, and CD57⁺ cells per mm² tumor tissue at baseline was significantly higher in responding patients compared with nonresponding patients (P = 0.01, P = 0.008, P = 0.015, and P < 0.001, respectively). During the first course of immunotherapy, the absolute number of CD4⁺, CD8⁺, and CD57⁺ cells per mm² tumor tissue was significantly higher in responding patients compared with nonresponding patients (P = 0.034, P < 0.001, and P < 0.001, respectively). However, no correlation was observed between the number of intratumoral lymphocytes and tumor FasL expression level.

Conclusion: These observations do not support the hypothesis that FasL tumor "counterattack" has an effect on the clinical outcome in metastatic renal cell carcinoma during IL-2–based immunotherapy.

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