Limits...
Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival

View Article: PubMed Central - PubMed

ABSTRACT

On a broader scale, T cell density and localization in colorectal cancer liver metastases have prognostic and predictive implications. As T cell distribution at higher resolutions has not been fully investigated, a detailed resolution analysis of T cell distribution was performed. Patient tissues were divided into 10 µm distance classes between the tumor border and adjacent normal liver. Thereby, distinct density patterns of T cell localization in relation to the malignant tissue could be detected. At a distance of 20 to 30 µm to the tumor, a decrease of CD3 T cells is common. Within this area, cytotoxic Granzyme B and CD8+ T cells were found to be significantly reduced as well as CD163 macrophages were increased and identified to be in close contact with T cells. Our data suggests a physical or functional border within this region. Survival analysis revealed improved overall survival in patients with high T cells numbers at the direct tumor border. Interestingly, the decreased T cells in the 20 to 30 µm region were also found to be significantly associated with improved survival. Consequently, the detailed localization of T cells, despite blockade, could be associated with improved clinical outcome. The high-resolution analysis represents new insights into relevant heterogenous T cell distributions especially related to clinical responses. As the paradoxical observation of localization-dependent prognostic relevance of T cell densities is only detectable by detailed spatial analyses, this investigation of spatial profiles at higher resolutions is suggested as a new biomarker for survival and response to therapies.

No MeSH data available.


Related in: MedlinePlus

Immunofluorescent double staining for CD163 (red) and PD-L1 (green) at the invasive margin. Dashed lines separate the tumor (top left) from the adjacent liver. DAPI was used as counterstain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5384380&req=5

f0008: Immunofluorescent double staining for CD163 (red) and PD-L1 (green) at the invasive margin. Dashed lines separate the tumor (top left) from the adjacent liver. DAPI was used as counterstain.

Mentions: In the course of this analysis, we further wanted to understand whether CD163 cells achieve immunosuppressive effects against T cells. We hypothesized that both cell types might be in close contact with each other and therefore analyzed the localization of T cells in relation to CD163 macrophages using serial section analysis (Fig. 7). We identified that 52–81% (median 68%) of CD3 lymphocytes within the tumor microenvironment were in close contact (< 10 µm) with CD163 macrophages. In addition, immunofluorescent double staining of CD163 and programmed death-ligand 1 (PD-L1) showed that the majority of CD163 macrophages were PD-L1 positive (Fig. 8).Figure 7.


Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival
Immunofluorescent double staining for CD163 (red) and PD-L1 (green) at the invasive margin. Dashed lines separate the tumor (top left) from the adjacent liver. DAPI was used as counterstain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384380&req=5

f0008: Immunofluorescent double staining for CD163 (red) and PD-L1 (green) at the invasive margin. Dashed lines separate the tumor (top left) from the adjacent liver. DAPI was used as counterstain.
Mentions: In the course of this analysis, we further wanted to understand whether CD163 cells achieve immunosuppressive effects against T cells. We hypothesized that both cell types might be in close contact with each other and therefore analyzed the localization of T cells in relation to CD163 macrophages using serial section analysis (Fig. 7). We identified that 52–81% (median 68%) of CD3 lymphocytes within the tumor microenvironment were in close contact (< 10 µm) with CD163 macrophages. In addition, immunofluorescent double staining of CD163 and programmed death-ligand 1 (PD-L1) showed that the majority of CD163 macrophages were PD-L1 positive (Fig. 8).Figure 7.

View Article: PubMed Central - PubMed

ABSTRACT

On a broader scale, T cell density and localization in colorectal cancer liver metastases have prognostic and predictive implications. As T cell distribution at higher resolutions has not been fully investigated, a detailed resolution analysis of T cell distribution was performed. Patient tissues were divided into 10&nbsp;&micro;m distance classes between the tumor border and adjacent normal liver. Thereby, distinct density patterns of T cell localization in relation to the malignant tissue could be detected. At a distance of 20 to 30&nbsp;&micro;m to the tumor, a decrease of CD3 T cells is common. Within this area, cytotoxic Granzyme B and CD8+ T cells were found to be significantly reduced as well as CD163 macrophages were increased and identified to be in close contact with T cells. Our data suggests a physical or functional border within this region. Survival analysis revealed improved overall survival in patients with high T cells numbers at the direct tumor border. Interestingly, the decreased T cells in the 20 to 30&nbsp;&micro;m region were also found to be significantly associated with improved survival. Consequently, the detailed localization of T cells, despite blockade, could be associated with improved clinical outcome. The high-resolution analysis represents new insights into relevant heterogenous T cell distributions especially related to clinical responses. As the paradoxical observation of localization-dependent prognostic relevance of T cell densities is only detectable by detailed spatial analyses, this investigation of spatial profiles at higher resolutions is suggested as a new biomarker for survival and response to therapies.

No MeSH data available.


Related in: MedlinePlus