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

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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

(A) Representative invasive margin of a CRC liver metastasis with annotations (CD3 positive lymphocytes appear dark brown). (B) The invasive margin of liver metastases is analyzed separately, encompassing 100 µm into normal adjacent liver from the tumor epithelium. Shaded areas highlight distinct distance classes of 10 µm in relation to the tumor epithelium.
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f0001: (A) Representative invasive margin of a CRC liver metastasis with annotations (CD3 positive lymphocytes appear dark brown). (B) The invasive margin of liver metastases is analyzed separately, encompassing 100 µm into normal adjacent liver from the tumor epithelium. Shaded areas highlight distinct distance classes of 10 µm in relation to the tumor epithelium.

Mentions: The classification of the 10 µm distance classes within the 100 µm area between the tumor and adjacent liver as outlined in Fig. 1 and the following cell quantification analyses could be performed successfully for all 36 patients. Thereby, bar plots for all distance classes were generated. This revealed distinct patterns that were detectable within each patient. For CD3, T cell quantification representative results of different patients are shown in Fig. S1. Apparently, CD3 T cells are located in all distance classes with maximum densities at different distances.Figure 1.


Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival
(A) Representative invasive margin of a CRC liver metastasis with annotations (CD3 positive lymphocytes appear dark brown). (B) The invasive margin of liver metastases is analyzed separately, encompassing 100 µm into normal adjacent liver from the tumor epithelium. Shaded areas highlight distinct distance classes of 10 µm in relation to the tumor epithelium.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0001: (A) Representative invasive margin of a CRC liver metastasis with annotations (CD3 positive lymphocytes appear dark brown). (B) The invasive margin of liver metastases is analyzed separately, encompassing 100 µm into normal adjacent liver from the tumor epithelium. Shaded areas highlight distinct distance classes of 10 µm in relation to the tumor epithelium.
Mentions: The classification of the 10 µm distance classes within the 100 µm area between the tumor and adjacent liver as outlined in Fig. 1 and the following cell quantification analyses could be performed successfully for all 36 patients. Thereby, bar plots for all distance classes were generated. This revealed distinct patterns that were detectable within each patient. For CD3, T cell quantification representative results of different patients are shown in Fig. S1. Apparently, CD3 T cells are located in all distance classes with maximum densities at different distances.Figure 1.

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