CCR5 status and metastatic progression in colorectal cancer

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Meggy Suarez-Carmona - , Deutsches Krebsforschungszentrum (DKFZ), Universität Heidelberg, Helmholtz-Institute for Translational Oncology Mainz (HI-TRON Mainz) (Autor:in)
  • Pornpimol Chaorentong - , Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Jakob Nikolas Kather - , Universität Heidelberg, RWTH Aachen University (Autor:in)
  • Rebecca Rothenheber - , Universität Heidelberg (Autor:in)
  • Azaz Ahmed - , Universität Heidelberg (Autor:in)
  • Anna Berthel - , Universität Heidelberg (Autor:in)
  • Anita Heinzelmann - , Universität Heidelberg (Autor:in)
  • Rodrigo Moraleda - , Universität Heidelberg, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Nektarios A. Valous - , Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Zeynep Kosaloglu - , Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Rosa Eurich - , Universität Heidelberg (Autor:in)
  • Jana Wolf - , Universität Heidelberg (Autor:in)
  • Silke Grauling-Halama - , Deutsches Krebsforschungszentrum (DKFZ), Universität Heidelberg, Helmholtz-Institute for Translational Oncology Mainz (HI-TRON Mainz) (Autor:in)
  • Michael Hundemer - , Universität Heidelberg (Autor:in)
  • Felix Lasitschka - , Universität Heidelberg (Autor:in)
  • Fee Klupp - , Universität Heidelberg (Autor:in)
  • Christoph Kahlert - , Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Alexis Ulrich - , Universität Heidelberg (Autor:in)
  • Martin Schneider - , Universität Heidelberg (Autor:in)
  • Christine Falk - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • Dirk Jäger - , Universität Heidelberg, Helmholtz-Institute for Translational Oncology Mainz (HI-TRON Mainz) (Autor:in)
  • Inka Zoernig - , Universität Heidelberg, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Niels Halama - , Deutsches Krebsforschungszentrum (DKFZ), Universität Heidelberg, Helmholtz-Institute for Translational Oncology Mainz (HI-TRON Mainz) (Autor:in)

Abstract

Multiple reports have highlighted the importance of the local immunological cellular composition (i.e. the density of effector T cells and macrophage polarization state) in predicting clinical outcome in advanced metastatic stage of colorectal cancer. However, in spite of the general association between a high effector T cell density and improved outcome, our recent work has revealed a specific lymphocyte-driven cancer cell-supporting signal. Indeed, lymphocyte-derived CCL5 supports CCR5-positive tumor cell proliferation and thereby fosters tumor growth in metastatic liver lesions. Upon systematic analysis of CCR5 expression by tumor cells using immunohistochemistry, we observed that the intensity of CCR5 increases with primary tumor size and peaks in T4 tumors. In liver metastases however, though CCR5 expression intensity is globally heightened compared to primary tumors, alterations in the expression patterns appear, leading to “patchiness” of the stain. CCR5 patchiness is, therefore, a signature of liver metastases in our cohort (n = 97 specimens) and relates to globally decreased expression intensity, but does not influence the extent of the response to CCR5 inhibitor Maraviroc in patients. Moreover, CCR5 patchiness relates to a poor immune landscape characterized by a low cytotoxic-to-regulatory T cell ratio at the invasive margin and enriched cellular and molecular markers of macrophage M2 polarization. Finally, because higher numbers of PD-1- and CTLA-4-positive cells surround tumors with patchy CCR5 expression, one can speculate that these tumors potentially respond to immune checkpoint blockade. This hypothesis is corroborated by the prolonged disease-free survival and disease-specific survival observed in patients with low gene expression of CCR5 in metastases from two publically available cohorts. These observations highlight the complex role of the CCL5-CCR5 axis in CRC metastatic progression and warrant further investigations.

Details

OriginalspracheEnglisch
Aufsatznummere1626193
FachzeitschriftOncoimmunology
Jahrgang8
Ausgabenummer9
PublikationsstatusVeröffentlicht - 2 Sept. 2019
Peer-Review-StatusJa

Externe IDs

PubMed 31428524

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • CCL5, CCR5, colorectal cancer, disease free survival, immune checkpoint, immunotherapy, macrophages, microenvironment, T cells