Rapid Autopsy to Define Dendritic Cell Spatial Distribution and T Cell Association in Lung Adenocarcinoma
Hilal Ozakinci1, Xiaofei Song2, Gina S Nazario1
1Thoracic Oncology Department, Moffitt Cancer Center, Tampa, FL.
Insights
Conventional dendritic cells (cDCs) impact immunotherapy. This study maps cDC distribution in lung adenocarcinoma, revealing distinct roles and site-specific variations in the tumor microenvironment (TME), offering therapeutic insights.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Immunotherapy efficacy correlates with conventional dendritic cell (cDC) presence.
- cDC type 1 (cDC1) drives CD8+ T cell activation, cDC type 2 (cDC2) influences CD4+ T cell responses, and regulatory cDCs can suppress anti-tumor immunity.
- Limited knowledge exists on human cDC distribution within the tumor microenvironment (TME), their prevalence in metastatic sites, and stage-dependent variations.
Purpose of the Study:
- To investigate the spatial distribution and prevalence of cDCs and other immune cells within the human lung adenocarcinoma TME.
- To compare cDC populations across different metastatic sites (lung, lymph node, liver).
- To analyze differences in cDC and immune cell proportions between early- and late-stage lung adenocarcinoma.
Main Methods:
- Utilized rapid autopsy specimens from 10 lung adenocarcinoma patients.
- Employed multiplex immunofluorescence with 18 markers to analyze 42 tumors.
- Quantified T cells, cDC1, cDC2, mature regulatory DCs, and macrophages.
Main Results:
- T cells, cDC1, and cDC2 were primarily located in the stroma, while mature regulatory DCs were enriched within the tumor.
- Lung and lymph node tumors showed higher enrichment of T cells and cDCs compared to liver tumors.
- Late-stage disease exhibited increased proportions of cDC2 and macrophages, unlike T cells and cDC1 which remained consistent across stages.
Conclusions:
- cDC subsets display distinct localization patterns within the lung adenocarcinoma TME, suggesting specialized functions.
- Metastatic site influences the immune cell composition, with liver metastases showing less immune infiltration.
- Stage-dependent alterations in cDC2 and macrophage populations indicate evolving immune regulation in advanced lung adenocarcinoma, with potential therapeutic implications.
Abstract:
Immunotherapy response is associated with the presence of conventional dendritic cells (cDCs). cDC type 1 (cDC1) is critically important for CD8+ T cell activation, cDC type 2 (cDC2) regulates CD4+ T cell responses, and mature regulatory cDCs may dampen T cell responses in the tumor microenvironment (TME). However, we lack a clear understanding of cDC distribution in the human TME, cDC prevalence in metastatic sites, and cDC differences in early- versus late-stage disease. Rapid autopsy specimens of 10 patients with lung adenocarcinoma were evaluated to detect cDCs and immune cells via multiplex immunofluorescence using 18 markers and 42 tumors. First, we found that T cells, cDC1, and cDC2 were confined to stroma, whereas mature regulatory DCs were enriched in tumor, suggesting unique localization-specific functions. Second, lung and lymph node tumors were more enriched in T cells and cDCs than liver tumors, underscoring differences in the TME of metastatic sites. Third, although the proportion of T cells and cDC1 did not differ in different stages, an increase in the proportion of cDC2 and macrophages in late stage suggests potential differences in regulation of T cell responses in different stages. Collectively, these findings provide new, to our knowledge, insights into cDC biology in human cancer that may have important therapeutic implications.
