Introduction: Numerous 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). Although CAFs are implicated in tumor progression, their total depletion of CAFs has been demonstrated to induce more aggressive tumors, indicating that different CAF subpopulations have opposing tumor-promoting or tumor-inhibitory roles. Unfortunately, specific markers to target these subsets of CAFs are lacking. Expression of the immune checkpoint CD70 is normally tightly regulated and limited to cells of the lymphoid lineage only. Instead, tumors hijack CD70 to facilitate immune evasion by increasing the amount of suppressive regulatory T cells (Tregs), inducing T cell apoptosis and skewing T cells towards T cell exhaustion. Recently, a lot of clinical successes have been generated by the blockade of immune checkpoints. However, in colorectal cancer (CRC) the efficacy remains limited to a small subset of patients with mismatch repair-deficient (MSI) tumors which might be caused by the intense dialogue between stroma and malignant cells. Therefore, we have explored the expression patterns of the immune checkpoint molecule CD70 in CRC, with a particular focus on CAFs.

Methods: The prognostic value of CD70 was analyzed by immunohistochemistry on 51 CRC specimens. In addition, the relationship with Tregs and microsatellite instability was explored. Furthermore, primary CAF cell lines were successfully cultured from 20 different primary resection specimens. These cell lines were 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 such as metastasis (P=0.007), differentiation (P=0.053) and advanced stage (P=0.001). Moreover, CD70-positive CAFs proved to be a poor prognostic marker by univariate as well as multivariate analysis. We have also detected a significant association between elevated Treg amounts and CD70-expressing CAFs (P=0.012). In vitro data on the effects of CD70 on CRC behavior and immune escape are currently being analyzed.

Conclusion: 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. The lack of association of CD70 expression and MSI-status, which highlights the potential of this target in CRC subsets that do not benefit from immune checkpoint blockade. We believe that targeting CD70 holds great potential in CRC, especially in light of the limited immunotherapeutic options available.

Citation Format: Julie Jacobs, Vanessa Deschoolmeester, Karen Zwaenepoel, Christophe Hermans, Christian Rolfo, Marc Peeters, Filip Lardon, Vasiliki Siozopoulou, Evelien Smits, Patrick Pauwels. Blocking CD70+ cancer associated fibroblasts: Are we paving the way towards immunotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 958. doi:10.1158/1538-7445.AM2017-958