Melanomas lacking HLA class I expression and response to checkpoint inhibitor.

Abstract

9553 Background: The current paradigm of how checkpoint inhibitors (CPIs) mediate anti-tumor effects relies on αβ T cells as the effector cells. However, HLA class I allele expression loss is common in melanoma, and in some cases, both β2-microglobulin (β2m) alleles are silenced, which results in complete loss of HLA I expression. We reasoned that if CPI therapy requires αβ T cells as the effector cells, melanoma tumors with biallelic loss of β2m could not present antigen to αβ T cells and should never respond to CPI. Methods: We screened the 2754 melanoma patients (pts) whose tumors had been genotypically analyzed using MSK-IMPACT, a hybridization capture-based next-generation assay for targeted deep sequencing of all exons and selected introns of up to 505 genes, including β2m. We identified 13 pts who had been treated with CPI, were evaluable for response and progression-free survival, and whose pre-treatment melanoma was found to have biallelic loss of β2m. In 1 pt, only a post-treatment tumor was available for genetic testing for β2m loss but lack of β2m expression in a pre-treatment tumor was confirmed by immunohistochemistry (IHC). Pts were assessed for clinical responses using RECIST 1.1. We recorded best overall response, duration of response, and overall survival. When available, pre-treatment tumor tissue was assessed by IHC for β2m and HLA class I expression, and for lymphocytic infiltrates expressing CD3, CD4, CD8, and CD56. Results: Anti-tumor responses were observed in 3/13 patients (23%); 2 PRs, 1 metabolic CR lasting for 24, 9.4, and 6.4 months, respectively. Responses were to ipilimumab (ipi) (N=2) and ipi/nivolumab (N=1). One pt responding to ipi had progressed on pembrolizumab; the other 2 responders were treatment-naïve. One pt died 11.5 months after starting treatment; the other 2 pts remain alive 5.5 and 8.9 years after starting treatment. IHC confirmed the lack of cell surface expression of β2m and HLA class I in all 5 tumors available for IHC staining. IHC evaluations of lymphocyte infiltrates in tumors from 1 responder and 4 non-responders showed variable degrees of CD3+ tumor infiltrating lymphocytes (TIL) with CD4+ T cell predominance. Interestingly, the 1 responder had the least dense pretreatment TIL among the 5 cases. In all 5 tumors, CD56+ lymphocytes, indicating NK cells, were rare-to-absent. Conclusions: Melanomas lacking HLA class I expression can respond to CPI therapy. Although all patients ultimately progressed, some responses were long-lived and 2 of 3 patients remain alive >5yrs. It seems unlikely that traditional CD8+ T cells are mediating these responses but more work needs to be done to identify the effector cells in these cases.