title: Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival.
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.
authors.affiliation: Clinical Cooperation Unit "Applied Tumor Immunity," National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Berthel
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Inka
authors.initials: I
authors.lastname: Zoernig
authors.affiliation: Clinical Cooperation Unit "Applied Tumor Immunity," National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Nektarios A
authors.initials: NA
authors.lastname: Valous
authors.affiliation: Department of Surgery, University Hospital Dresden , Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of Surgery, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Fee
authors.initials: F
authors.lastname: Klupp
authors.affiliation: Department of Surgery, University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Ulrich
authors.affiliation: Department of Surgery, University Hospital Dresden , Dresden, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Clinical Cooperation Unit "Applied Tumor Immunity," National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jaeger
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
keywords: Colorectal cancer liver metastases; T cell distribution; immunosuppression; prognosis; tumor immunology; tumor microenvironment