CD95-mediated tumor recognition by CD4⁺ effector cells in a murine mammary model

The authors examined cellular mechanisms involved in anti-tumor reactivity induced by the murine MT-9G1 mammary tumor line, which was transduced to secrete granulocyte macrophage-colony-stimulating factor (GM- CSF). Compared with the parental MT-901 tumor, MT-9G1 subcutaneous tumors elicited an influx of CD4⁺ cells and dendritic cells. Secondary in vitro activation of tumor-draining lymph node cells with anti-CD3 and interleukin-2 resulted in effector cells that can mediate regression of established pulmonary metastases after adoptive transfer. In vivo depletion of T-cell subsets showed that tumor regression required CD4⁺ tumor-draining lymph node cells rather than CD8⁺ cells. The activated CD4⁺ cells expressed CD95L and mediated lysis of CD95⁺ MT-901 tumor cells, which were major histocompatibility complex class II negative. The CD4⁺ cells also released GM-CSF in response to tumor stimulation. A Fas fusion protein inhibited tumor lysis and GM-CSF release by the CD4⁺ cells. These studies document an alternate pathway by which CD4⁺ immune cells may recognize major histocompatibility complex class II-deficient tumors in which CD95L-bearing T cells induced an anti-tumor response mediated via CD95L:CD95.