PD-1+ polyfunctional T cells dominate the periphery after tumor-infiltrating lymphocyte therapy for cancer
2017
Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating
lymphocytes (TILs) can result in tumor regression of exceptional duration. Initial tumor regression
has been associated with persistence of tumor-specific TILs one 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 sixteen 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 post-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 which 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.
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