Tumor immunity in perforin-deficient mice: a role for CD95 (Fas/APO-1)

Area of Science:

• Immunology
• Cancer Biology
• Cellular Cytotoxicity

Background:

• Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells employ two primary cytocidal pathways: perforin/granzyme-mediated and CD95 ligand (CD95L)/CD95-mediated killing.
• Perforin-dependent killing requires effector cell expression, while CD95-mediated killing necessitates target cell CD95 (Fas/APO-1) expression.
• The role of these pathways in tumor immune surveillance, particularly in the context of perforin deficiency, remains incompletely understood.

Purpose of the Study:

• To investigate the contribution of perforin-independent, CD95-mediated cytotoxicity to tumor immune surveillance.
• To examine the expression of CD95 on tumor cells in vitro and in vivo.
• To elucidate the mechanisms by which CTL/NK cells control tumor growth in the absence of perforin.

Main Methods:

• Utilized perforin-deficient mice to study immunity against the Lewis lung carcinoma 3LL tumor and its sublines (D122 and Kb39.5).
• Assessed CD95 expression on tumor cells cultured in vitro and grown in vivo.
• Examined tumor growth and immune responses in syngeneic and allogeneic mouse models.

Main Results:

• Perforin-independent CD95L/CD95 pathway demonstrated efficacy against high (D122) and low (Kb39.5) metastatic 3LL sublines.
• Tumor cells, initially lacking surface CD95 in vitro, exhibited significantly up-regulated CD95 expression when grown in vivo.
• Enhanced CD95 expression was also observed on other tumor types (LF-, BW, P815) in vivo, suggesting a general phenomenon.

Conclusions:

• CD95-dependent, perforin-independent immunity contributes to the control of certain tumors, particularly at early stages of growth.
• Up-regulation of CD95 on tumor cells in vivo indicates the activation of this pathway during anti-tumor immune responses.
• Progressive down-regulation of CD95 expression during tumor progression may represent a tumor escape mechanism.