Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage.
The efficacy of immune response to control human cancer remains controversial. It is particularly debated whether and to what extent the capacity of tumor-infiltrating dendritic cells (DC) to drive immunization can be turned off by transformed cells, leading to tumor-specific tolerance rather than immunization. To address this issue, we have characterized the DC isolated from human non-small cell lung cancer (NSCLC). These biopsy specimens contained CD11c(high) myeloid DC (mDC), but also CD11c(-) plasmacytoid DC (pDC) and a third DC subset expressing intermediate level of CD11c. Compared with peripheral blood, CD11c(high) tumor-infiltrating DC (TIDC) displayed a "semi-mature" phenotype, and TLR4 or TLR8 stimulation drove them to mature partially and to secrete limited amounts of cytokines. In contrast, most tumor-infiltrating pDC were immature but underwent partial maturation after TLR7 activation, whereas TLR9 ligation triggered low secretion of IFN-alpha. CD11c(int) mDC represented approximately 25% of total DC in tumoral and peritumoral tissues and expressed low levels of costimulatory molecules contrasting with high levels of the immunoinhibitory molecule B7-H1. Finally, the poor APC function of total TIDC even after TLR stimulation and the migratory response of both tumor-infiltrating mDC and pDC toward CCL21 and SDF-1 in vitro suggested their ability to compromise the tumor-specific immune response in draining lymph nodes in vivo. Further studies will be required to establish the specific role of the three TIDC subsets in tumor immunity and to draw conclusions for the design of therapeutic strategies.
Perrot
Ivan
I
Laboratory for Immunological Research, Schering-Plough, Dardilly, France.
Blanchard
Dominique
D
Freymond
Nathalie
N
Isaac
Sylvie
S
Guibert
Benoît
B
Pachéco
Yves
Y
Lebecque
Serge
S
D039521:CD11c Antigen / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000628:therapy; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000276:immunology; D019743:Chemokines, CXC / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D022423:Myeloid Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape; D014611:Vaccination
C515478:CCL21 protein, human; D039521:CD11c Antigen; C515255:CXCL12 protein, human; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; D051193:Toll-Like Receptors