PO-306 Targeting CD70-positive cancer associated fibroblasts to tackle the immune suppressive tumour microenvironment in colorectal cancer

Abstract

IntroductionTumour progression and invasiveness are determined not only by the malignant cancer cells themselves but also by the surrounding tumour microenvironment, comprising of cancer-associated fibroblasts (CAFs). CAFs represent a heterogeneous population with both cancer-promoting and cancer-restraining actions, lacking specific markers to target them. Expression of the immune checkpoint CD70 is normally tightly regulated and limited to cells of the lymphoid lineage. Instead, tumours 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. In this study, we aimed at exploring the expression patterns of CD70 in colorectal cancer (CRC), not merely focusing on the tumour cells, but also taking the tumour microenvironment into account.Material and methodsWe have analysed the prognostic value of CD70 expression by immunohistochemistry in CRC specimens and studied its relationship with well-known fibroblast markers, microsatellite instability and Tregs. Furthermore, primary CAF cell lines were used to study the role of CD70 on migration and immune escape.Results and discussionsWe revealed prominent expression of CD70 on a specific subset of CAFs in invasive CRC specimens. Cancer cells show almost no expression of CD70. CD70+ CAFs proved to be an independent adverse prognostic marker. Functionally, CD70+ CAFs stimulated migration and significantly increased the frequency of naturally occurring Tregs. Finally, experiments aimed at therapeutically targeting these CD70-positive CAFs are currently being analysed using 2D and 3D models.ConclusionWe have identified the expression of CD70 on CAFs as a novel prognostic marker for CRC. Performing this research, we 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 our ongoing exploration of CD70-targeting antibodies in CRC, especially in light of the limited immunotherapeutic options available in CRC.