Abstract
CD8(+) T cells at the earliest stage of effector generation have not been identified at tumor site of melanoma patients. Such early effectors, if present, should be characterized by a specific phenotype, distinct from that expressed at later stages of the antigen-induced differentiation program, by short-lived effector cells, memory precursors, and terminal effectors. Here, we show that neoplastic tissues from primary and metastatic lesions of melanoma patients contain a subset of CD8(+) T cells expressing FOXP3. CD8(+) FOXP3(+) CD25(+) T lymphocytes were found in tumor-invaded lymph nodes (TILN), s.c. metastases, and advanced primary lesions. Their frequency was significantly higher in TILN compared with tumor-free lymph nodes or with peripheral blood and in primary tumors compared with TILN. CD8(+) FOXP3(+) T cells did not express markers of regulatory [CTLA-4, CCL4, interleukin-10 (IL-10), transforming growth factor-β1], exhausted (PD-1), or senescent (CD57) CD8(+) T lymphocytes. Instead, this subset showed an antigen-experienced "EM1" phenotype (CCR7(-) CD45RA(-) CD28(+) CD27(+)) and exhibited a CD127(-), KLRG1(-), HLA-DR(+), CD38(+), T-bet(+), perforin(+) "early effector" profile predicted by current models. CD8(+) FOXP3(+) T cells produced IFN-γ on short in vitro activation, recognized autologous tumor by CD107a mobilization, and expressed Ki-67 on ex vivo analysis. In response to autologous tumor plus IL-2/IL-15, the CD8(+) FOXP3(+) T cells proliferated promptly and showed competence for differentiation (downregulation of CD27 and upregulation of T-bet). These results suggest development of early phases of antitumor immunity even in advanced melanoma. Moreover, the CD8(+) FOXP3(+) "early effector" subset may be an invaluable tool for monitoring immunity at tumor site.
Highlights
Antigen-experienced, melanoma-specific effector memory (TEM) and terminally differentiated (TEMRA) CD8+ T lymphocytes have been found at high frequencies in tumor-invaded lymph nodes (TILN) compared with tumor-free lymph nodes (TFLN) and with peripheral blood of advanced melanoma patients
CD8+ Early Effector T Cells in Melanoma and function can be found at tumor site of melanoma patients, we looked for the presence in such tissues of CD8+ T lymphocytes expressing the forkhead/winged helix transcription factor FOXP3
CD8+ FOXP3+ frequency was significantly higher in these tissues than in TILN, but not in s.c. metastases
Summary
Antigen-experienced, melanoma-specific effector memory (TEM) and terminally differentiated (TEMRA) CD8+ T lymphocytes have been found at high frequencies in tumor-invaded lymph nodes (TILN) compared with tumor-free lymph nodes (TFLN) and with peripheral blood of advanced melanoma patients (see ref. 1 for review and refs. 2, 3). According to several current models [6,7,8,9,10], mainly based on analysis of CD8+ response to viral infection, an encounter with antigen activates a differentiation program in naïve CD8+ T cells that initially generates early effectors with a KLRG1− CD127− phenotype. These early effectors can adopt different cell fates, depending on antigen density and duration of TCR stimulation, extent of interleukin-2 (IL-2) receptor signaling [11], type of antigen presenting cells, and presence of inflammatory cytokines. Effectors can differentiate to CD127lo KLRG1+ short-lived effector cells (SLEC) or to CD127hi KLRG1− memory precursors (MPEC)
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