Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome.
Immunohistochemical analysis of FOXP3 in primary breast tumors showed that a high number of tumor-infiltrating regulatory T cells (Ti-Treg) within lymphoid infiltrates surrounding the tumor was predictive of relapse and death, in contrast to those present within the tumor bed. Ex vivo analysis showed that these tumor-infiltrating FOXP3(+) T cells are typical Treg based on their CD4(+)CD25(high)CD127(low)FOXP3(+) phenotype, their anergic state on in vitro stimulation, and their suppressive functions. These Ti-Treg could be selectively recruited through CCR4 as illustrated by (a) selective blood Treg CCR4 expression and migration to CCR4 ligands, (b) CCR4 down-regulation on Ti-Treg, and (c) correlation between Ti-Treg in lymphoid infiltrates and intratumoral CCL22 expression. Importantly, in contrast to other T cells, Ti-Treg are selectively activated locally and proliferate in situ, showing T-cell receptor engagement and suggesting specific recognition of tumor-associated antigens (TAA). Immunohistochemical stainings for ICOS, Ki67, and DC-LAMP show that Ti-Treg were close to mature DC-LAMP(+) dendritic cells (DC) in lymphoid infiltrates but not in tumor bed and were activated and proliferating. Furthermore, proximity between Ti-Treg, CD3(+), and CD8(+) T cells was documented within lymphoid infiltrates. Altogether, these results show that Treg are selectively recruited within lymphoid infiltrates and activated by mature DC likely through TAA presentation, resulting in the prevention of effector T-cell activation, immune escape, and ultimately tumor progression. This study sheds new light on Treg physiology and validates CCR4/CCL22 and ICOS as therapeutic targets in breast tumors, which represent a major health problem.
Gobert
Michael
M
INSERM, U590, Lyon F-69008, France.
Treilleux
Isabelle
I
Bendriss-Vermare
Nathalie
N
Bachelot
Thomas
T
Goddard-Leon
Sophie
S
Arfi
Vanessa
V
Biota
Cathy
C
Doffin
Anne Claire
AC
Durand
Isabelle
I
Olive
Daniel
D
Perez
Solène
S
Pasqual
Nicolas
N
Faure
Christelle
C
Ray-Coquard
Isabelle
I
Puisieux
Alain
A
Caux
Christophe
C
Blay
Jean-Yves
JY
Ménétrier-Caux
Christine
C
D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D001943:Breast Neoplasms / Q000276:immunology*; D002449:Cell Aggregation; D002465:Cell Movement; D054422:Chemokine CCL22 / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D019394:Ki-67 Antigen / Q000032:analysis; D008213:Lymphocyte Activation; D054398:Receptors, CCR4 / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D000945:Antigens, Differentiation, T-Lymphocyte; C515482:CCL22 protein, human; C515354:CCR4 protein, human; D054422:Chemokine CCL22; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D019394:Ki-67 Antigen; D054398:Receptors, CCR4