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)