The prognostic significance of CXCR4 and SDF-1 in differentiated thyroid cancer depends on CD8+ density

Alexander Wilhelm; Isabelle Lemmenmeier; Alexandros Lalos; Alberto Posabella; Venkatesh Kancherla; Salvatore Piscuoglio; Tarik Delko; Markus von Flüe; Kathrin Glatz; Raoul André Droeser

doi:10.1186/s12902-022-01204-2

The prognostic significance of CXCR4 and SDF-1 in differentiated thyroid cancer depends on CD8+ density

BMC Endocr Disord. 2022 Nov 23;22(1):292. doi: 10.1186/s12902-022-01204-2.

Authors

Alexander Wilhelm^#^{1

2}, Isabelle Lemmenmeier^#³, Alexandros Lalos³, Alberto Posabella³, Venkatesh Kancherla⁴, Salvatore Piscuoglio^{4

5}, Tarik Delko^{3

6}, Markus von Flüe^{3

5}, Kathrin Glatz⁴, Raoul André Droeser³

Affiliations

¹ Department of Surgery, Clarunis, St. Clara Hospital and University Hospital Basel, University of Basel, Basel, Postfach, 4002, Switzerland. alexander.wilhelm@clarunis.ch.
² Department of Surgery, University of California, San Francisco, CA, USA. alexander.wilhelm@clarunis.ch.
³ Department of Surgery, Clarunis, St. Clara Hospital and University Hospital Basel, University of Basel, Basel, Postfach, 4002, Switzerland.
⁴ Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
⁵ Visceral Surgery Research Laboratory, Clarunis, Department of Biomedicine, Basel, Switzerland.
⁶ Department of Surgery, Hirslanden Hospital St. Anna, Lucerne, Switzerland.

^# Contributed equally.

Abstract

Background: Tumor infiltration with cytotoxic CD8+ T-cells is associated with a favorable outcome in several neoplasms, including thyroid cancer. The chemokine axis CXCR4/SDF-1 correlates with more aggressive tumors, but little is known concerning the prognostic relevance in relation to the tumor immune microenvironment of differentiated thyroid cancer (DTC).

Methods: A tissue microarray (TMA) of 37 tumor specimens of primary DTC was analyzed by immunohistochemistry (IHC) for the expression of CD8+, CXCR4, phosphorylated CXCR4 and SDF-1. A survival analysis was performed on a larger collective (n = 456) at RNA level using data from The Cancer Genome Atlas (TCGA) papillary thyroid cancer cohort.

Results: Among the 37 patients in the TMA-cohort, the density of CD8+ was higher in patients with less advanced primary tumors (median cells/TMA-punch: 12.5 (IQR: 6.5, 12.5) in T1-2 tumors vs. 5 (IQR: 3, 8) in T3-4 tumors, p = 0.05). In the TCGA-cohort, CXCR4 expression was higher in patients with cervical lymph node metastasis compared to N0 or Nx stage (CXCR4^high/low 116/78 vs. 97/116 vs. 14/35, respectively, p = 0.001). Spearman's correlation analysis of the TMA-cohort demonstrated that SDF-1 was significantly correlated with CXCR4 (r = 0.4, p = 0.01) and pCXCR4 (r = 0.5, p = 0.002). In the TCGA-cohort, density of CD8+ correlated with CXCR4 and SDF-1 expression (r = 0.58, p < 0.001; r = 0.4, p < 0.001). The combined marker analysis of the TCGA cohort demonstrated that high expression of both, CXCR4 and SDF-1 was associated with reduced overall survival in the CD8 negative TCGA cohort (p = 0.004).

Conclusion: These findings suggest that the prognostic significance of CXCR4 and SDF-1 in differentiated thyroid cancer depends on the density of CD8 positive T-lymphocytes. Further studies with larger sample sizes are needed to support our findings and inform future investigations of new treatment and diagnostic options for a more personalized approach for patients with differentiated thyroid cancer.

Keywords: CD8; CXCR4; Chemokines; Differentiated thyroid cancer; SDF-1; Tumor microenvironment.

MeSH terms

Adenocarcinoma*
CD8-Positive T-Lymphocytes / metabolism
Chemokine CXCL12 / metabolism
Humans
Prognosis
Receptors, CXCR4 / genetics
Thyroid Cancer, Papillary / genetics
Thyroid Neoplasms* / diagnosis
Thyroid Neoplasms* / genetics
Thyroid Neoplasms* / metabolism
Tumor Microenvironment

Substances

CXCR4 protein, human
Receptors, CXCR4
Chemokine CXCL12