Unveiling a CD70-positive subset of cancer-associated fibroblasts marked by pro-migratory activity and thriving regulatory T cell accumulation

Julie Jacobs; Vanessa Deschoolmeester; Karen Zwaenepoel; Tal Flieswasser; Christophe Deben; Jolien Van den Bossche; Christophe Hermans; Christian Rolfo; Marc Peeters; Olivier De Wever; Filip Lardon; Vasiliki Siozopoulou; Evelien Smits; Patrick Pauwels

doi:10.1080/2162402X.2018.1440167

Unveiling a CD70-positive subset of cancer-associated fibroblasts marked by pro-migratory activity and thriving regulatory T cell accumulation

Oncoimmunology. 2018 Mar 19;7(7):e1440167. doi: 10.1080/2162402X.2018.1440167. eCollection 2018.

Authors

Julie Jacobs^{1

2}, Vanessa Deschoolmeester^{1

2}, Karen Zwaenepoel^{1

2}, Tal Flieswasser^{1

2}, Christophe Deben^{1

2}, Jolien Van den Bossche¹, Christophe Hermans^{1

2}, Christian Rolfo^{1

3

4}, Marc Peeters^{1

3}, Olivier De Wever⁵, Filip Lardon¹, Vasiliki Siozopoulou², Evelien Smits^{1

6}, Patrick Pauwels^{1

2}

Affiliations

¹ Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.
² Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, Edegem, Belgium.
³ Department of Oncology, Antwerp University Hospital, Edegem, Belgium.
⁴ Phase 1-Early Clinical Trials Unit, Antwerp University Hospital, Wilrijkstraat 10, Edegem, Belgium.
⁵ Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, De Pintelaan 185, Ghent University Hospital, Ghent, Belgium.
⁶ Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.

Abstract

Cancer-associated fibroblasts (CAFs) are involved in the proliferative and invasive behavior of colorectal cancer (CRC). Nonetheless, CAFs represent a heterogeneous population with both cancer-promoting and cancer-restraining actions, lacking specific markers to target them. Expression of the immune checkpoint molecule CD70 is normally limited to cells of the lymphoid lineage. Instead, tumor cells hijack CD70 to facilitate immune evasion by increasing the amount of suppressive regulatory T cells (Tregs). The aim of this study was to explore CD70 expression patterns in CRC, not merely focusing on the tumor cells, but also taking the tumor stromal cells into account. We have analyzed the prognostic value of CD70 expression by immunohistochemistry in CRC specimens and its relationship with well-known fibroblast markers and Tregs. In addition, in vitro experiments were conducted to unravel the role of CD70-positive CAFs on migration and immune escape. We reveal prominent expression of CD70 on a specific subset of CAFs in invasive CRC specimens. Cancer cells show almost no expression of CD70. The presence of CD70-positive CAFs proved to be an independent adverse prognostic marker. Functionally, CD70-positive CAFs stimulated migration and significantly increased the frequency of naturally occurring Tregs. In conclusion, we have identified the expression of CD70 on CAFs as a novel prognostic marker for CRC. We have found evidence of a cross talk between CD70⁺ CAFs and naturally occurring Tregs, paving the way towards immune escape. As such, this study provides a strong rationale for the exploration of CD70-targeting antibodies in CRC.

Keywords: CD70; Cancer-associated fibroblasts; biomarker; colorectal cancer; immunotherapy; migration; prognosis; regulatory T cells; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by the agency for Flanders Innovation & Entrepreneurship under Grant number 120–128. In addition, part of this research was supported by the Flemish Gastroenterology Association, Belgian Group of Digestive Oncology, Kom op tegen Kanker (Stand up to Cancer), the Flemish cancer society, the University of Antwerp (BOF-KP) and a private donation by Mr. Willy Floren (Schilde, Belgium).