Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. One of its hallmarks is thick, dense tissue made primarily of cancer-associated fibroblasts (CAF) that surround the tumor. Several research groups have reported the distinctive roles of CAF in inflammation and cancer cell growth (1). A study published in Cancer Cell recently shed new light on their unusual behavior (2).
“All kinds of cancer have been sequenced, [and] people found that almost every cancer type consists of multiple populations of CAF,” said Huocong Huang, a molecular biochemist at the University of Texas Southwestern Medical Center. By using a combination of single-cell RNA sequencing and an in vivo lineage tracing method, Huang and his team identified a unique population of antigen-presenting CAF (apCAF) that originates from mesothelial cells (2).
Huang was particularly interested in apCAF because they express major histocompatibility complex class two (MHC-II), which is typically found only in antigen-presenting immune cells such as dendritic cells (3). Antigen-presenting cells with MHC Class II can alert pathogen-killing immune cells. It was unclear whether apCAF could also perform these functions.
“If these apCAF have MHC Class II, they must be talking to the immune system,” said Ela Elyada, a molecular biologist at Hebrew University of Jerusalem who was not involved in the study. Elyada’s own past work hinted at the possibility of apCAF activating CD4 T cells, which coordinate downstream immune responses (4).
Elyada explained that, unlike normal antigen-presenting cells, apCAF lack the machinery needed for activating these T cells. Without that machinery, it wasn’t clear what the results of their interactions would be, or what the cells were doing with MHC-II proteins.
Huang and his team found that apCAF do no activate CD4 T cells. Instead, these fibroblasts transform CD4 T cells into regulatory T cells (Tregs), which suppresses the antitumor immune response.
“This activity adds another layer of complexity to what CAF do,” said Neta Erez, a cancer biologist at Tel Aviv University who was not involved in this study.
Understanding the function of different CAF could inform the design of future immunotherapies, such as immune checkpoint inhibitors. “Tregs are highly associated with immune evasion or the response to immune checkpoint blockade. So, if we can further identify the mechanism and intervene [in] this biologically, we may potentially have some new [strategies] to target the immune suppression or enhance the efficacy of immune checkpoint blockade,” said Huang.
According to Elyada, oncologists are looking into immunotherapy as a treatment option for pancreatic cancer. However, the success rate is still fairly low compared to that for other cancers. “Pancreatic cancer is what people often call [a] cold tumor. They don’t have a lot of T cells to start with,” she said. Elyada speculated that inhibiting apCAF could prove useful to enhance T cell activation.
Inhibiting apCAF will need to be combined with another kind of intervention that can attract T cells to the tumor site to induce killing. “Cancer cells secrete all kinds of things that repel the T cells,” she said. “It's not going to help you if the T cells are not there.”
In addition to examining the function of apCAF, Huang and his team also performed lineage tracing of single cells and analyzed published single-cell RNA sequencing datasets to identify the origin of apCAF in PDAC. “The beautiful thing is they were able to show that this specific subpopulation [of CAF] comes from the layer of mesothelium,” said Erez.
Pinning down the origin of apCAF is important for getting closer to targeting these potentially harmful cells. Mesothelial cells are easily missed because of their seemingly basic role of lining the surface cavity of vital organs. “Actually, I’d never heard of mesothelial cells before this study,” said Huang. His team later discovered that targeting mesothelin, a protein formed by mesothelial cells, stopped these cells from turning into apCAF in mice implanted with pancreatic cancer.
Treating cancer by targeting mesothelin is not a new concept (5). In fact, mesothelin, a tumor-associated antigen that is overexpressed in many types of tumors, was one of the first cancer cell-specific antigens that scientists identified. From this discovery, scientists developed antibody-drug conjugates, a class of drug in which an antibody is chemically attached to a drug to guide it to mesothelin-expressing tumor cells (6).
“There are a lot of trials right now trying to target mesothelin-positive cells as cancer cell markers,” said Huang. Yet, his finding suggested that an antibody against mesothelin might show effects beyond targeted killing of tumor cells. These antibodies could be useful for targeting apCAF, which could in turn ameliorate the Treg upregulation and increase the number of CD4 T cells.
Huang said that while the findings are promising, translational success could be a long way away. For now, the clinical focus is still on detecting pancreatic cancer as early as possible, which he thinks is very difficult and challenging. “You can probably inhibit mesothelial cell differentiation [in the early stages of cancer], but the patients usually only come in at a pretty late stage when the tumor has already formed.” Without this early diagnosis, implementing these interventions may not help.
Huang is now investigating the interaction of apCAF with different cancer cell types to identify any novel signaling pathways, which may lead to new therapeutic targets.
References
- Lavie, D. et al. Cancer-associated fibroblasts in the single-cell era. Nat Cancer 3, 793–807 (2022).
- Huang, et al. Mesothelial cell-derived antigen-presenting cancer associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer, Cancer Cell 40, 656–673 (2022).
- Roche, P. and Furuta, K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol 15, 203–216 (2015).
- Elyada, E. et al. Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts. Cancer Discov 9, 1102–1123 (2019).
- Faust, J. R. et al. Mesothelin: An Immunotherapeutic Target beyond Solid Tumors Cancers 14, 1550 (2022).
- Rottey, S. et al. Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors. Clin Cancer Res 28, 95–105 (2022).
