774 Analysis of the tumor reactivity of tumor-infiltrating lymphocytes in a metastatic melanoma lesion that lost MHC class I expression after anti-PD-1 therapy

Abstract

Several mechanisms for delayed relapses in melanoma patients long after the initial positive responses to anti-PD-1 therapy have been suggested. These include the escape of tumor cells from the immune system. However, the tumor-specific reactivity of TILs in the escaped tumor lesion, especially after MHC-class-I- loss has not been well evaluated. A 55-year-old Japanese woman with metastatic melanoma in her left supraclavicular lymph node and left accessory nerve lymph node was started on treatment with anti-PD-1 antibody therapy. Tumor progression was prevented by the therapy for 12 months. However, then one metastatic lesion started to grow again despite ongoing response in another lesion and the absence of new metastatic sites. We found no remarkable differences in the phenotypes of freshly isolated TILs from the two sites. Immunohistochemistry showed that MHC class I expression was diminished in the relapsed lesion. The tumor cell line established from the lesion also lost MHC class I expression completely. The copy-number assay revealed a deletion of the B2M gene. When we transduced the normal B2M gene into these cells, we confirmed the recovery of MHC class I molecule expression on their surface. Next, we expanded TILs from the left accessory nerve lymph node lesion and, assessed their reactivity to the autologous tumor cell line, with or without B2M gene transduction. We verified that TILs derived from the relapsed lesion could strongly recognize the autologous tumor cells in a MHC-class I-dependent manner. Our report emphasizes the limitations of T-cell-based immunotherapy and highlights the importance of developing alternative strategies for such cases.