期刊
CLINICAL CANCER RESEARCH
卷 23, 期 19, 页码 5779-5788出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-1692
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资金
- Danish Cancer Society
- Capital Region of Denmark Research Foundation
- Danielsen Foundation
- The Danish Cancer Society [R172-A10970, R149-A10124, R90-A6139] Funding Source: researchfish
Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8(+) T-cell populations in patients with metastatic melanoma following treatment with TILs. Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8(+) T cells contained in serial blood samples of 16 patients treated with TILs. Results: Polyfunctional tumor-reactive CD8(+) T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD-1, and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8(+) T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8(+) T cells, further analyses showed that CD8(+) T cells specific for defined tumor antigens had similar differentiation status. Conclusions: We demonstrated that tumor-reactive CD8(+) T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1(+) polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2-mediated inhibition. (C) 2017 AACR.
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