Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage
Ivan Perrot1, Dominique Blanchard, Nathalie Freymond
1Laboratory for Immunological Research, Schering-Plough, Dardilly, France.
Abstract:
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.
Insights
Tumor-infiltrating dendritic cells (DC) in non-small cell lung cancer (NSCLC) show impaired immune function. These cells may suppress anti-tumor immunity, hindering effective cancer treatment strategies.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- The role of the immune system, particularly dendritic cells (DCs), in controlling human cancer is debated.
- Tumor cells may induce immune tolerance by inhibiting the ability of tumor-infiltrating DCs (TDCs) to initiate anti-tumor immune responses.
Purpose of the Study:
- To characterize the phenotype and function of DCs isolated from human non-small cell lung cancer (NSCLC) tumors.
- To investigate whether TDCs can be driven to mature and secrete cytokines upon stimulation, and to assess their potential to compromise anti-tumor immunity.
Main Methods:
- Isolation and characterization of three distinct DC subsets (CD11c(high) mDC, CD11c(-) pDC, CD11c(int) mDC) from NSCLC biopsy specimens.
- Assessment of DC maturation and cytokine secretion following Toll-like receptor (TLR) stimulation (TLR4, TLR8, TLR7, TLR9).
- Evaluation of antigen-presenting cell (APC) function and migratory responses (toward CCL21 and SDF-1) in vitro.
Main Results:
- CD11c(high) TDCs exhibited a semi-mature phenotype, with limited cytokine secretion upon TLR4/TLR8 stimulation.
- Tumor-infiltrating pDCs were mostly immature, with partial maturation upon TLR7 activation and low IFN-alpha secretion via TLR9.
- CD11c(int) mDCs expressed low costimulatory molecules and high levels of the inhibitory B7-H1 molecule. Total TDCs showed poor APC function and migrated towards chemokines, suggesting immune suppression.
- The poor APC function of total TDCs even after TLR stimulation and the migratory response of both tumor-infiltrating mDCs and pDCs toward CCL21 and SDF-1 in vitro suggested their ability to compromise the tumor-specific immune response in draining lymph nodes in vivo.
Conclusions:
- Tumor-infiltrating DCs in NSCLC display an impaired phenotype and function, potentially contributing to immune evasion.
- The characterized DC subsets may hinder effective anti-tumor immune responses.
- Further research is needed to elucidate the specific roles of TDCs in tumor immunity and to inform therapeutic strategies.
