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

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, 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.

Biomarkers for cancer-associated fibroblasts

“…Moreover, CAFs expressing CD70 enrich regulatory T cells to invasive colorectal cancer and CD70 expression is negatively correlated with survival of patients with colorectal cancer ( Fig. 1b) [47]. PDPN seems to be a potential therapeutic target while CD70 and vimentin might be more suitable for prognostic indicators and more evidences are warranted.…”

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

“…These results all indicate that potential crosstalk between CAFs and Treg cells might exist. Evidence of the interaction between CD70 + CAFs and naturally occurring Tregs has already been reported [ 208 ]. In a study of colorectal cancer, researchers revealed that CAFs stimulate the migratory activity of Treg cells and markedly increase their frequency in tumor sites [ 208 ].…”

Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy

“…In vitro studies show CD70 + CAFs isolated from invasive colorectal cancer specimens stimulate the migration of Tregs. Meanwhile, the expression of CD70 on CAFs is proved to be an independent adverse prognostic marker for colorectal cancer [113]. Bone marrow-derived CAFs can also inhibit allogeneic T cell responses through IDO production [114].…”