The role of host B7-H1 in the recurrence of B16 melanoma. (TUM9P.1013)

Abstract Our B16 melanoma mouse model, in which ~50% of mice receiving adoptive cellular therapy with cytolytic CD4+ T cells recognizing the tumor/self antigen tyrosinase protein 1 (TRP-1), exhibits tumor relapse following initial tumor regression. CD4+ T cells from tumor-bearing TRP-1 antigen knockout (tyrp1BwRAG-/-) transgenic mice, or tumor sensitized (t.s.) T cells, expressed low levels of the exhaustion marker PD-1 and were 15-25% Foxp3+. Due to this presensitization, B16 tumors recurred faster and more predictably in RAG-/- mice with t.s. CD4+ T cells than naïve TRP-1-specific CD4+ T cells. However, in RAG-/- mice lacking B7-H1 (i.e. PD-L1, the ligand for PD-1), relapses occurred more rarely and developed at slower rates following adoptive transfer of t.s. CD4+ T cells. When CD4+ T cells from mice bearing relapsing tumors, expressing high levels of PD-1 and Foxp3+, were transferred into either RAG-/- or B7-H1-/-RAG-/- mice, the treatment effect was completely abrogated. We previously reported that primary tumors required B7-H1 blockade or Treg depletion to be treated, and relapsing tumors required both treatments. Here we show that Treg cell depletion in B7-H1-/-RAG-/- mice partially restored treatment with fully exhausted CD4+ T cells and relapses took longer to occur. These data indicate that although multiple mechanisms are involved in tumor recurrence (Treg cells and PD-1), the expression of B7-H1 in the host rather than the tumor plays a major role in B16 melanoma relapse.