Role of CAFs in Tumor Growth and Immune Suppression

Cancer-associated fibroblasts (CAF) are a prevalent cell population in the microenvironment of pancreatic cancer. The pancreas harbors diverse resident cell populations that can differentiate into CAFs, and the cell of origin might contribute to CAF heterogeneity. Expression of the transcription factor Wilms tumor 1 (WT1) marks mesothelial cells as well as a transcriptionally distinct population of fibroblasts in the normal pancreas. WT1 expression also identifies a population of CAFs in both human and mouse pancreatic cancers. In this study, we investigated the contribution of WT1+ mesenchymal cells to CAF populations and evaluated the functional role of WT1+ stromal cells in pancreatic cancer. Lineage tracing revealed that WT1+ cells expand in pancreatic cancer, giving rise to a population of inflammatory CAFs. Depletion of WT1+ stromal cells reduced orthotopic tumor growth, with increased immunosuppressive macrophage activation and reduced infiltration of CD8+ and FOXP3+ T cells. Notably, the reduction in tumor weight observed with WT1+ cell depletion was independent of CD8+ and CD4+ T cells. WT1+ CAFs expressed high levels of tumor-promoting ligands that likely interact directly with the tumor epithelium to drive tumor progression. Accordingly, WT1-expressing cell–depleted tumors had reduced epithelial MAPK activation. Together, these data show that WT1+ stromal cells represent a tumor-promoting CAF population. Although this population might constitute a potential therapeutic target, caution will be needed to avoid exacerbating immune suppression. Paper and research by Allison B. and larger team at University of Michigan 

Targeting CAFs via CAR T cell therapy in pancreatic murine models - Here, the authors treated established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). - Depletion of FAP+ CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. - Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape. - These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials. https://lnkd.in/e9JeC8bM #cancerresearch #celltherapy #tumormicroenvironment #fibrosis #pancreaticcancer

🧩 Cancer’s biggest trick? Turning the immune system against itself. This figure illustrates how cancer cells in epithelial–mesenchymal plasticity (EMP) states exploit the immune microenvironment—especially through TGF-β signaling—to tip the balance away from killing tumors and toward protecting them. 🔹 Panel A: Dendritic cells & CD8+ T cells Normally, these are the “frontline soldiers” of anti-tumor defense. But cancer cells express PD-L1 and secrete TGF-β, dampening CD8+ T cell activity while boosting regulatory T cells (Tregs) that suppress immunity. 🔹 Panel B: Natural Killer (NK) cells NK cells should destroy tumor cells with granzymes and perforin. Yet EMP cancer cells block NK cell activation (via NKG2D, DAP12, miR-183) while—again—TGF-β drives Tregs to dominate. 🔹 Panel C: Macrophages & CAFs EMP cancer cells recruit M2 macrophages (pro-tumor type) and cancer-associated fibroblasts (CAFs), which flood the space with immunosuppressive molecules (CXCL12, IL-10, TGF-β). This further weakens CD8+ T cells. 🔹 Panel D: The big picture TGF-β is the central switch: ✨ Promotes anti-tumor immune cells when balanced (CD8+ T cells, NK cells, dendritic cells, M1 macrophages). ⚠️ Drives pro-tumor immune responses when hijacked (Tregs, M2 macrophages, CAFs, Th17 cells). 👉 The takeaway: cancer doesn’t just avoid the immune system—it rewires it. Understanding this immune tug-of-war opens the door for smarter immunotherapies that block TGF-β’s pro-tumor effects while restoring the body’s natural defenses. 💡 Question: If you could “flip” one immune switch in the tumor microenvironment, would you target TGF-β… or go after its downstream players like Tregs and M2 macrophages? #Immunotherapy #CancerResearch #TumorMicroenvironment #Oncology #ImmuneEvasion *Made with BioRender for Educational Reasons*

Some tumors are not “cold” by default—they’re kept cold on purpose, by their stroma. Gao et al.’s cross-tissue fibroblast atlas in Cancer Cell takes us past the usual “CAF-high vs CAF-low” narrative and shows, in detail, which fibroblast states build immune barricades and which actually scaffold anti-tumor immunity. It’s a rare example of single-cell data that doesn’t stop at pretty UMAPs, but instead maps fibroblast lineages into concrete stromal failure modes—immune-excluded, matrix-dense niches versus Treg-rich, immunosuppressive hubs—and ties them to survival and immunotherapy response. If we’re still designing trials around a single CAF score in 2026, we’re leaving a lot of therapeutic leverage on the table. This atlas offers something better: a vocabulary to say what kind of stromal problem a tumor has—and how to design combinations that actually fit the underlying biology.

Why do COX-inhibitors like aspirin and celecoxib help prevent and treat colorectal cancer (CRC)? Our new preprint suggests part of the answer is that they work as ‘anti-plasticity’ drugs. In CRC, tumours with a fibroblast-rich (stromal) microenvironment do worse. Dozens of stromal–epithelial signals have been described, but their relative importance has been unclear. Combining high-throughput single-cell organoid perturbations, a novel single-cell co-culture CRISPR screening platform, and spatial transcriptomics of human CRC, we show that fibroblast-derived prostaglandin E2 (PGE2) is the dominant stromal regulator of CRC cell-fate plasticity. We report three main findings: 1) DACH1 Marks Stromal-reprogramming Competence. We developed a way to quantify CAF-induced plasticity in CRC epithelia and found that the transcriptional co-repressor DACH1 marks which cells are susceptible to CAFs: DACH1+ epithelia respond to stromal signals, DACH1– epithelia don't. 2) Intercellular Single-cell Secretome CRISPR Screening. We next developed a novel single-cell arrayed CRISPR perturbation platform to interrogate native cell-cell communication in solid cancer models. By perturbing the CAF secretome and measuring the plasticity response in CRC epithelia, we identified CAF PTGS2 (COX2) as a major regulator of epithelial cell-fate. Full factorial analysis revealed that PGE2 is not just another intercellular communication ligand, but the functionally dominant CAF-derived regulator of epithelial cell-fate across the CAF secretome. PGE2 rapidly and reversibly converts chemosensitive proliferative colonic stem cells (proCSCs) into chemorefractory, pro-metastatic revival colonic stem cells (revCSCs), and this effect can be suppressed by aspirin. 3) PTGS2+ CAFs Map a Spatial Plasticity Gradient in Human CRC. In primary human CRC tumours, spatial transcriptomics revealed that PTGS2+ CAFs organise a local epithelial plasticity gradient anchored by increasing DACH1 expression. Specifically, epithelia <200 µm from PTGS2+ CAFs are revCSC and epithelia >200 µm are proCSC in all tumours tested. This links stromal prostaglandin signalling to poor-prognosis cell-fates in vivo. -> Together, we propose a causal, spatial mechanism for how inflammatory stromal niches grant non-genetic access to therapy-resistant, metastatic cell fates — and a mechanistic rationale for COX inhibition (aspirin/celecoxib) in both preventing and treating CRC. This paper was led by two fantastic PhD students, Corinne Molyneux & Rhianna O'Sullivan, and supported by many in Tape Lab. It was a huge pleasure to work with CRC-STARS collaborators Eoghan Mulholland-Illingworth, PhD, Joshua Moore, and Simon Leedham, and Raheleh Amirkhah and Philip Dunne — plus Smita Krishnaswamy and Jeroen Claus, who added their usual magic. This work stands on decades of research across the CRC stem-cell, stromal, and prostaglandin fields. https://lnkd.in/ekvUT-b2