PD-1 Identifies Patient-Specific CD8-Positive Tumor-Infiltrating Lymphocytes in Melanoma

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Adoptive transfer of tumor-infiltrating lymphocytes can mediate regression of metastatic melanoma. However, there are no effective markers to identify and select patient-specific repertoires of tumor-reactive and mutation-specific CD8-positive lymphocytes, limiting the ability to develop strategies to increase clinical efficacy and extend such therapy to other malignancies.

In a study reported in Journal of Clinical Investigation, Gros and colleagues assessed unique phenotypic traits of CD8-positive tumor-infiltrating lymphocytes and T-cell receptor β chain clonotypic frequency in 6 melanoma tumors in the attempt to identify patient-specific repertoires of the tumor-reactive CD8-positive lymphocytes. In all tumors, expression of the inhibitory receptors PD-1 (CD279), lymphocyte-activation gene 3 (LAG-3, CD223), and T-cell immunoglobulin and mucin domain 3 (TIM-3) on CD8-positive tumor-infiltrating lymphocytes identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8-positive lymphocytes. In contrast, only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (CD137).

Deep sequencing of T-cell receptor β chain showed oligoclonal expansion of specific T-cell receptor β chain clonotypes in CD8-positive/PD-1–positive vs CD8-positive/PD-1–negative tumor-infiltrating lymphocyte populations. The T-cell receptor β chain clonotypes in the CD8-positive and the CD8-positive/PD-1–positive populations that exhibited the greatest expansion recognized autologous tumor and included clonotypes that targeted mutated antigens.

The investigators concluded, “[I]n addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on [CD8-positive] tumor-infiltrating lymphocytes] also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.” ■

Gros A, et al: J Clin Invest 124:2246-2259, 2014.