Tumor-infiltrating lymphocyte subsets and tertiary lymphoid structures in pulmonary metastases from colorectal cancer

Clinical & Experimental Metastasis, Jul 2016

The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) reflects an active inflammatory tumor microenvironment. High density of TILs as well as presence of TLS is associated with improved survival in various solid cancer types. We aimed to describe the density and distribution of TILs and TLS in pulmonary metastases (PMs) from primary colorectal cancer (CRC) and its correlation with clinicopathological variables. Fifty-seven CRC pulmonary metastasectomy specimen (PM) and 31 matched primary CRC specimen were included. Cluster of differentiation (CD)3+, CD8+, CD45RO+ and FoxP3+ TILs were evaluated by immunohistochemistry and density was scored semiquantitatively. TLS were evaluated based on morphological criteria. Survival time was defined from pulmonary metastasectomy to death or last follow up. A marked infiltration with CD3+, CD8+, CD45RO+ and FoxP3+ TILs was evident in CRC PM and matched primary CRC. Further assessment of the immune infiltrate in PM showed that a high density of FOXP3+ TILs at the invasive margin [HR 2.40 (1.11–6.96); P = 0.031] and low density of CD8+ cells in TLS [HR 0.30 (0.14–0.79); P = 0.016] were associated with a worse prognosis in univariate analysis. Moreover, a low CD8/FoxP3-ratio of TILs at the invasive margin (P = 0.042) and in TLS (P = 0.027) conferred an impaired prognosis after pulmonary metastasectomy. Our findings suggest that CRC PM harbor an immune active microenvironment. The balance of CD8+ and FoxP3+ T-cells at the tumor border and in TLS provides prognostic information in patients with CRC PM.

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Tumor-infiltrating lymphocyte subsets and tertiary lymphoid structures in pulmonary metastases from colorectal cancer

Clin Exp Metastasis Tumor-infiltrating lymphocyte subsets and tertiary lymphoid structures in pulmonary metastases from colorectal cancer Thomas Schweiger 0 1 2 3 4 5 Anna Sophie Berghoff 0 1 2 3 4 5 Christoph Glogner 0 1 2 3 4 5 Olaf Glueck 0 1 2 3 4 5 Orsolya Rajky 0 1 2 3 4 5 Denise Traxler 0 1 2 3 4 5 Peter Birner 0 1 2 3 4 5 Matthias Preusser 0 1 2 3 4 5 Walter Klepetko 0 1 2 3 4 5 Konrad Hoetzenecker 0 1 2 3 4 5 0 Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna , Vienna , Austria 1 Division of Thoracic Surgery, Department of Thoracic Surgery, Medical University of Vienna , Waehringer Guertel 18-20, 1090 Vienna , Austria 2 & Konrad Hoetzenecker 3 Department of Pathology, Medical University of Vienna , Vienna , Austria 4 Comprehensive Cancer Center, Medical University of Vienna , Vienna , Austria 5 Department of Medicine I, Medical University of Vienna , Vienna , Austria The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) reflects an active inflammatory tumor microenvironment. High density of TILs as well as presence of TLS is associated with improved survival in various solid cancer types. We aimed to describe the density and distribution of TILs and TLS in pulmonary metastases (PMs) from primary colorectal cancer (CRC) and its correlation with clinicopathological variables. Fifty-seven CRC pulmonary metastasectomy specimen (PM) and 31 matched primary CRC specimen were included. Cluster of differentiation (CD)3?, CD8?, CD45RO? and FoxP3? TILs were evaluated by immunohistochemistry and density was scored semiquantitatively. TLS were evaluated based on morphological criteria. Survival time was defined from pulmonary metastasectomy to death or last follow up. A marked infiltration with CD3?, CD8?, CD45RO? and FoxP3? TILs was evident in CRC PM and matched primary CRC. Further assessment of the immune infiltrate in PM showed that a high density of FOXP3? TILs at the invasive margin [HR 2.40 (1.11-6.96); P = 0.031] and low density of CD8? cells in TLS [HR 0.30 (0.14-0.79); P = 0.016] were associated with a worse prognosis in univariate analysis. Moreover, a low CD8/FoxP3-ratio of TILs at the invasive margin (P = 0.042) and in TLS (P = 0.027) conferred an impaired prognosis after pulmonary metastasectomy. Our findings suggest that CRC PM harbor an immune active microenvironment. The balance of CD8? and FoxP3? T-cells at the tumor border and in TLS provides prognostic information in patients with CRC PM. Pulmonary metastasis; Colorectal cancer; Tumor-infiltrating lymphocytes; TILs; Tertiary lymphoid structures Background Despite advances in the early detection and treatment of colorectal cancer (CRC), the prognosis of patients is impaired as soon as distant metastases occur. Synchronous pulmonary spreading is evident in about one out of ten patients with newly diagnosed CRC. Subsequently, an average 5-year cumulative risk of 5.8 % for the development of metachronous pulmonary metastases (PMs) is additionally contributing to the disease burden of patients with CRC [ 1 ]. However, within the group of patients with CRC lung metastases long-term survival can be achieved by (repeated) pulmonary metastasectomy complemented by chemotherapeutic regimens. In contrast, some patients will present with diffuse recurrence of disease within months after pulmonary metastasectomy. The underlying tumor biology is considered to be the main cause for heterogeneity in the outcome of patients with CRC lung metastases. Several prognostic biomarkers have been proposed to define aggressive tumors associated with fatal outcome [ 2–4 ]. During the last years, the tumor microenvironment gained increasing attention in the scientific community, especially in groups focusing on metastatic CRC [ 5–7 ]. Immune escape is considered an emerging hallmark of cancer [ 8 ]. Various subsets of lymphocytes can be found in the tumor microenvironment, so called tumor-infiltrating lymphocytes (TILs). They can launch pro-inflammatory anti-tumor responses or mediate local immunosuppression. The amount of TILs has a prognostic value in various primary solid cancer types, including lung, renal, breast and CRC [ 9–14 ]. Commonly detected lymphocyte subsets with favorable prognostic impact are mature T-cells [cluster of differentiation (CD)3?] and cytotoxic T-cells (CD8?), memory-T-cells (CD45RO?), while immune suppressive regulatory T-cells (FoxP3?) are associated with impaired prognosis. Moreover, tertiary lymphoid structures (TLSs), which are ectopic lymphoid aggregates present in chronically inflamed tissue, can be found in the tumor stroma. TLS are believed to promote and maintain inflammation and anti-tumor response similar to secondary lymphoid organs. The presence of TLS in the tumor microenvironment is associated with favorable prognosis especially in CRC [ 15, 16 ]. So far little is known about the local immune response in CR (...truncated)


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Thomas Schweiger, Anna Sophie Berghoff, Christoph Glogner, Olaf Glueck, Orsolya Rajky, Denise Traxler, Peter Birner, Matthias Preusser, Walter Klepetko, Konrad Hoetzenecker. Tumor-infiltrating lymphocyte subsets and tertiary lymphoid structures in pulmonary metastases from colorectal cancer, Clinical & Experimental Metastasis, 2016, pp. 727-739, Volume 33, Issue 7, DOI: 10.1007/s10585-016-9813-y