Tumor-reactive CD8+ early effector T cells identified at tumor site in primary and metastatic melanoma

Andrea Anichini, Alessandra Molla, Claudia Vegetti, Ilaria Bersani, Roberta Zappasodi, Flavio Arienti, Fernando Ravagnani, Andrea Maurichi, Roberto Patuzzo, Mario Santinami, Hanspeter Pircher, Massimo Di Nicola, Roberta Mortarini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)8378-8387
Number of pages10
JournalCancer Research
Volume70
Issue number21
DOIs
Publication statusPublished - Nov 1 2010

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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