Authors
J. JACOBS (1), V. DESCHOOLMEESTER (2), K. ZWAENEPOEL (3), C. HERMANS (2), C. ROLFO (4), M. PEETERS (5), F. LARDON (2), V. SIOZOPOULOU (6), E. SMITS (2), P. PAUWELS (7) / [1] University of Antwerp, Antwerp, Belgium, center for oncological research (CORE), [2] University of Antwerp, Antwerp, Belgium, Center for oncological research (CORE), [3] ANTWERP UNIVERSITY HOSPITAL, Edegem, Belgium, pathology, [4] ANTWERP UNIVERSITY HOSPITAL, Edegem, Belgium, Phase 1-early clinical trials unit, [5] ANTWERP UNIVERSITY HOSPITAL, Edegem, Belgium, Oncology, [6] ANTWERP UNIVERSITY HOSPITAL, Edegem, Belgium, Pathology, [7] University of Antwerp, Antwerp, Belgium, Pathology
Introduction
Several studies have reported that tumor progression and invasiveness are determined not only by the malignant cancer cells themselves but also by the surrounding tumor microenvironment, including cancer-associated fibroblasts (CAFs). On the other hand, a total depletion of CAFs marks more aggressive tumor, indicating that different CAF subpopulations have opposing tumor-promoting or tumor-inhibitory roles. Unfortunately, markers to identify these different subsets of CAFs are lacking. It has been described that tumors hijack the immune checkpoint molecule CD70 to facilitate immune evasion by increasing the amount of suppressive regulatory T cells (Tregs). Nevertheless, the expression patterns of CD70 in colorectal cancer (CRC) have never been described before.
Aim
Due to the lack of specific markers to target CAFs with tumor-promoting properties and the limited clinical successes of immune checkpoint blockade in CRC, we have examined the expression pattern of CD70 in CRC with a particular focus on CAFs.
Methods
The expression of CD70 was analyzed by immunohistochemistry on 51 CRC specimens and linked with clinicopathological parameters. In addition, an association of CD70 with Tregs (CD4+FOXP3+) was explored. Finally, a primary CAF cell line was used to study the effect of CD70 on the tumor microenvironment in vitro.
Results
We revealed expression of CD70, not just on the malignant cells but on the majority of CAFs in invasive CRC specimens. Thereby, CD70-expression was significantly correlated with negative clinicopathological parameters including liver metastasis (P=0.007), differentiation (P=0.053) and advanced stage (P=0.001). In addition, CD70-positive CAFs proved to be an independent prognostic marker for inferior overall survival and progression-free survival. We have also detected a significant association between Treg infiltration and CD70-expressing CAFs (P=0.012). In vitro data on the effects of CD70 on CRC behavior are currently being analyzed.
Conclusions
We have identified a new targetable CAF subpopulation, marked by the expression of CD70 and equipped with strong tumor-promoting properties. Thereby, we have found evidence of a potential cross talk between CD70+ CAFs and Treg, paving the way towards immune escape of the tumor. We believe that targeting CD70 holds great potential in CRC, especially in light of the limited immunotherapeutic options available in colorectal cancer.
