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

CTL and NK cells use two distinct cytocidal pathways: 1) perforin and granz yme based and 2) CD95L/CD95 mediated. The former requires perforin expressi on by the effecters (CTL or NK), whereas the latter requires CD95 (Fas/APO- 1) expression by the target. We have investigated how these two factors con tribute to tumor immune surveillance by studying the,immunity of perforin-d eficient mice against the progressor C57BL/6 Lewis lung carcinoma 3LL, whic h expresses no CD95 when cultured in vitro. Unexpectedly, the results indic ated that the perforin-independent CD95L/CD95 pathway of CTL/NK plays a rol e in acting against D122 and K(b)39.5 (39.5) high and low metastatic sublin es, respectively, derived from the 3LL tumor. Although no membrane-bound CD 95 was detected on cultured D122 and 39.5 cells, surface CD95 expression on both D122 and 39.5 was considerably up-regulated when the tumors were grow n in vivo. A similarly enhanced expression of CD95 was observed with three additional tumors; LF-, BW, and P815, injected into syngeneic and allogenei c mice. The finding of up-regulated CD95 expression on tumor cells placed i n vivo suggests that a CD95-based mechanism plays a role in tumor immunity at early stages of tumor growth. Consequently, the progressive down-regulat ion of CD95 expression during tumor progression may indeed be an escape mec hanism as previously reported. Together, these results suggest a role for C D95-dependent, perforin-independent immunity against certain tumors.