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Published on: November 26, 2010
ALCAM-mediated cDC1 CD8 T cells interactions are suppressed in advanced lung tumors
Luciano G Morosi1, Giulia M Piperno1, Lucía López1
1Cellular Immunology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
Abstract:
Conventional type 1 dendritic cells (cDC1) are critical regulators of anti-tumoral T-cell responses. The structure and abundance of intercellular contacts between cDC1 and CD8 T cells in cancer tissues is important to determine the outcome of the T-cell response. However, the molecular determinants controlling the stability of cDC1-CD8 interactions during cancer progression remain poorly investigated. Here, we generated a genetic model of non-small cell lung cancer crossed to a fluorescent cDC1 reporter (KP-XCR1venus) to allow the detection of cDC1-CD8T cell clusters in tumor tissues across tumor stages. We found that cDC1-CD8 clusters are abundant and productive at the early stages of tumor development but progressively diminish in advanced tumors. Transcriptional profiling and flow cytometry identified the adhesion molecule ALCAM/CD166 (Activated Leukocyte Cell Adhesion Molecule, ligand of CD6) as highly expressed by lung cDC1 and significantly downregulated in advanced tumors. Analysis of human datasets indicated that ALCAM is downregulated in non-small cell lung cancer and its expression correlates to better prognosis. Mechanistically, triggering ALCAM on lung cDC1 induces cytoskeletal remodeling and contact formation whereas its blockade prevents T-cell activation. Together, our results indicate that ALCAM is important to stabilize cDC1-CD8 interactions at early tumor stages, while its loss in advanced tumors contributes to immune evasion.
Insights
Activated Leukocyte Cell Adhesion Molecule (ALCAM) stabilizes crucial interactions between dendritic cells and T cells in early lung cancer. Its downregulation in advanced tumors promotes immune evasion.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Interactions
Background:
- Conventional type 1 dendritic cells (cDC1) are key regulators of anti-tumor T-cell responses.
- The stability of cDC1-CD8 T cell interactions is vital for anti-tumor immunity but poorly understood in cancer progression.
Purpose of the Study:
- To investigate the molecular mechanisms controlling cDC1-CD8 T cell interactions during non-small cell lung cancer progression.
- To identify factors that stabilize or destabilize these crucial immune cell contacts.
Main Methods:
- Generation of a genetic model of non-small cell lung cancer with fluorescent cDC1 reporters (KP-XCR1venus).
- Analysis of cDC1-CD8 T cell clusters in tumors across different stages.
- Transcriptional profiling and flow cytometry.
- Analysis of human non-small cell lung cancer datasets.
Main Results:
- cDC1-CD8 T cell clusters were abundant in early-stage tumors but diminished in advanced stages.
- Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) was highly expressed by cDC1 in early tumors and downregulated in advanced tumors.
- ALCAM downregulation in non-small cell lung cancer correlated with poorer prognosis in human datasets.
- ALCAM engagement promoted cDC1-CD8 T cell contact formation and T cell activation, while blockade inhibited it.
Conclusions:
- ALCAM is essential for stabilizing cDC1-CD8 T cell interactions in early lung cancer.
- Loss of ALCAM in advanced tumors contributes to immune evasion and reduced anti-tumor immunity.
- ALCAM represents a potential therapeutic target for enhancing anti-tumor responses.
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