Two mechanisms for tumor evasion of preexisting cytotoxic T-cell responses: Lessons from recurrent tumors

Tumors evade host immunity at both the induction and effector phases. Most studies have focused on tumor evasion at the induction phase, and, due in p art to poor antitumor CTL responses to most tumors, the mechanism for evasi on of CTL effector function is less clear. Here we have taken advantage of the strong CTL responses to a costimulator B7-1-transfected tumor to study the mechanism for tumor evasion of preexisting host immunity. We have inves tigated six independent recurrent tumors isolated from mice that were chall enged with and had rejected B7-1-transfected J558 (J558-B7) tumors. Because the mice had developed strong antitumor CTL responses, these recurrent tum ors must have evaded preexisting antitumor CTLs. Indeed, whereas the parent al J558-B7 cell line is efficiently lysed by the ex vivo tumor-infiltrating lymphocytes, all of the recurrent tumors are resistant to such Lysis. Inte restingly, the recurrent tumors can be divided into two groups. The group 1 tumors have vastly reduced levels of cell surface MHC class I with a concu rrent reduction in the expression of multiple genes devoted to MHC class I antigen presentation. In contrast, the group 2 tumors have Lost the express ion of costimulatory molecule B7-1 while retaining cell surface MHC class I and expression of all antigen presentation genes studied. These results de monstrate that tumors can evade preexisting CTLs either by avoiding present ation of the tumor antigen or, surprisingly, by down-regulation of costimul atory molecules. The paradoxical requirements of both antigen and costimula tory molecules at the effector phase raised an interesting question on the nature of antitumor immunity.