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.

MHC class I loss due to the abnormality of β2-microgloburin (B2M) gene is one of the mechanism underlying delayed relapses in melanoma patients long after the initial positive responses to anti-PD-1 therapy. However, the tumor-specific reactivity of tumor-infiltrating lymphocytes (TILs) in tumor lesions that lost MHC class I expression has not been well evaluated. We report the case of a 55-year-old woman with two metastatic melanoma lesions. After a 12-month period of successful tumor suppression by anti-PD-1 antibody therapy, one lesion started to grow again. We resected both lesions and examined the tumor cells and TILs. The shrinking lesion consisted of necrotic tissue and macrophages, and the enlarged lesion consisted of both necrotic tissue and viable tumor cells. The tumor cells completely lost MHC class I expression, but it was restored upon retroviral transduction of the normal B2M gene. When we checked the tumor-specific reactivity of TILs derived from the relapsing lesion, we found that these TILs failed to recognize the native tumor cells derived from the lesion, but strongly recognized the MHC-class-I-recovered cells by B2M transduction. Our report emphasizes the limitations of T-cell-based immunotherapy and highlights the importance of developing alternative strategies for such cases.