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Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.

Cancer-associated fibroblasts (CAFs) secrete and synthesize fibroblast activation protein (FAP), which could promote proliferation and immunosuppression of multiple cancers including esophageal squamous cell carcinoma (ESCC). CXCL12/CXCR4 signaling could be revitalized by CAFs in cancer cells. Nevertheless, the significance of this interaction in ESCC has yet to be elucidated. Herein, we investigated whether FAP + CAF cells could promote ESCC cells proliferation, migration and regulate immunity through the CXCL12/CXCR4 pathway in vitro and in vivo. The protein expression level of FSP1, FAP, CD8+ and Ki-67 in different sample was estimated by IHC and western blot. qPCR was used to quantify the mRNA level of FSP1, FAP, CD8+ and Ki-67 in different sample. The cell viability, proliferation, migration and invasion of different sample were evaluated by CCK-8, EdU staining, wound healing assay and Transwell assay, respectively. The ELISA was carried out to measure the protein level of IFN-γ, TNF-α, GZMB and IL-2. ESCC xenograft mice model was established to assess the impact of FAP+ CAF. FSP1, FAP, CD8+ and Ki-67 are greatly up-regulated in hESCC tissues. Through CXCL12/CXCR4 axis, FAP-positive CAF was capable of promoting the cell proliferation, migration and invasion of ESCC tumor cells and preventing the CD8+ T cells from secreting cytokine. Blocking this signaling with selective CXCR4 antagonist could counteract the effects caused by high-expression of FAP. FAP+ CAFs could inhibit the occurrence and development of tumors. These results indicated that FAP-positive CAF have an impact on cell proliferation migration and immunoregulation of ESCC through the CXCL12/CXCR4 axis.

Murine studies have shown that immunological targeting of fibroblast activation protein (FAP) can elicit protective immunity in the absence of significant pathology. Fibroblast activation protein is a product overexpressed by tumor‐associated fibroblasts (TAF) and is the predominant component of the stoma in most types of cancer. Tumor‐associated fibroblasts differ from normal adult tissue fibroblasts, and instead resemble transient fetal and wound healing‐associated fibroblasts. Tumor‐associated fibroblasts are critical regulators of tumorigenesis, but differ from tumor cells by being more genetically stable. Therefore, in comparison to tumor cells, TAF may represent more viable therapeutic targets for cancer immunotherapy. To specifically target TAF, we constructed a DNA vaccine directed against FAP. This vaccine significantly suppressed primary tumor and pulmonary metastases primarily through CD8+ T‐cell‐mediated killing in tumor‐bearing mice. Most importantly, tumor‐bearing mice vaccinated against FAP exhibited a 1.5‐fold increase in lifespan and no significant pathology. These results suggest that FAP, a product preferentially expressed by TAF, could function as an effective tumor rejection antigen. (Cancer Sci 2010; 101: 2325–2332)

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68 Ga/ 177 Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177 Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177 Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8 + T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177 Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177 Lu-LNC1004 for cancer patients with FAP-positive tumors.

Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAPα-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy.

Fibrotic interstitial lung disease (fILD), particularly idiopathic pulmonary fibrosis (IPF), represents an incurable progressive lung disorder characterized by a dismal prognosis. Fibroblasts constitute the principal cellular drivers of the fibrotic cascade. Although two pharmacological agents (pirfenidone and nintedanib) have secured regulatory approval for clinical application, they remain incapable of substantially attenuating disease progression. Persistent immune dysregulation driven alveolitis, occupies a critical upstream position in perpetuating fibroblast activation and extracellular matrix (ECM). Recent investigations have introduced an innovative strategy employing genetically engineered T cells to selectively target and eliminate activated fibroblasts. This approach involves generating chimeric antigen receptor (CAR) T cells in vivo by encapsulating mRNA encoding CARs within lipid nanoparticles (LNPs). These CAR T cells can specifically recognize and ablate fibroblasts expressing fibroblast activation protein (FAP). In this review, we summarize recently developed CAR T cell therapeutic strategies for IPF treatment with optimal targeting of FAP-fibroblasts, synthesize the existing preclinical studies and clinical trials evaluating anti-FAP CAR T cells to date, and critically discuss the adverse events associated with CAR T therapy alongside strategies to overcome current limitations of CAR T cell therapy in IPF management.

Fibroblast activation protein (FAP) overexpression on cancer-associated fibroblasts (CAFs) is associated with poor prognosis and worse clinical outcomes. Selective ablation of pro-tumorgenic FAP stromal cells with CAR-T cells may be a new therapeutic strategy. However, the clinical use of FAP-CAR T cells is suggested to proceed with caution for occasional poor efficacy and induction of on-target off-tumor toxicity (OTOT), including lethal osteotoxicity and cachexia. Hence, more investigations and preclinical trials are required to optimize the FAP-CAR T cells and to approve their safety and efficacy. In this study, we designed second-generation CAR T cells targeting FAP with 4-1BB as a co-stimulatory molecule, and tested their cytotoxicity against FAP-positive cells (hFAP-HT1080 cells and a variety of primary CAFs) and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model. Results showed that our FAP-CAR T cells were powerfully potent in killing human and murine FAP-positive tumor cells and CAFs in multiple types of tumors in BALB/c and C57BL/6 mice and in patient-derived xenografts (PDX) model. And they were proved to be biologically safe and exhibit low-level OTOT. Taken together, the human/murine cross-reactive FAP-CAR T cells were powerfully potent in killing human and murine FAP positive tumor cells and CAFs. They were biologically safe and exhibit low-level OTOT, warranting further clinical investigation into our FAP-CAR T cells.

Myocardial fibrosis is a common pathological feature in many cardiovascular diseases, yet effective targeted therapies remain elusive. Given the emerging potential of chimeric antigen receptor T (CAR-T) cell therapy in nononcological diseases and fibroblast activation protein (FAP) as a promising target, we engineered a second-generation FAP-targeted CAR construct incorporating the 4-1BB costimulatory domain to enhance therapeutic safety. Using two delivery approaches—lentiviral vectors and lipid nanoparticles (LNPs)—we generated FAP-CAR–engineered Jurkat cells as a preliminary screening model and evaluated their CAR expression, target recognition, and in vitro cytotoxic activity. These engineered cells selectively recognized and induced apoptosis in FAP-expressing cardiac myofibroblasts without triggering excessive IL-6 secretion, supporting their potential for fibrosis-selective cytotoxicity. Our findings provide key preliminary in vitro evidence supporting the design and target-specific functionality of FAP-targeted CAR constructs incorporating the 4-1BB domain, warranting further investigation in primary T cell models for cardiac fibrosis therapy.

The effects of stromal cell cultures isolated from breast cancer tissue on the differentiation and maturation of dendritic cells and proliferation of lymphocytes were studied in vitro . The derived cultures had the fibroblast-like morphology and carried mesenchymal markers CD73 and CD90 in the absence of epithelial (CD326, CD24) and macrophage (CD68) markers. The cells also expressed CD44, CD10, and CD29 and had low levels of HLA-ABC expression. Intracellular expression of fibroblast activation protein (FAP), tenascin C, and α-SMA indicated their activated state and stromal origin. Analysis of the functional properties of the cells revealed their ability to suppress differentiation of dendritic cells from monocytes, as well as the proliferation of T lymphocytes. However, they had no significant effect on DC maturation. The results demonstrate that fibroblasts in the tumor stroma of breast cancer may have a suppressive effect on important mechanisms of the adaptive immunity and can be involved in the process of tumor escape from the immunological control.

Background Chimeric Antigen Receptor (CAR)-T cells therapy has revolutionized the treatment of hematological cancers and are currently redirected towards non-malignant diseases. If correction of the gene defect remains the cornerstone of the treatment of Duchenne Muscular Dystrophy (DMD), the disease-associated fibrosis can limit its efficacy. We thus assessed the effects of eliminating cardiac fibrosis of DMD by CAR-T cells targeting Fibroblast Activation Protein (FAP), a protein strongly expressed by activated fibroblasts. Methods In vitro CAR-T cells expressing both FAP and a green fluorescent probe (GFP) were first co-cultured with FAP + of FAP- target cells to check for FAP-expressing lymphocyte activation. Then, anti-FAP CAR-T cells were intravenously delivered in a dystrophic murine model (D2. mdx ), following lymphodepletion, to investigate the kinetics, biodistribution, cardiac functional and anti-fibrotic effects of anti-FAP CAR-T cells compared with control lymphocytes engineered to only express GFP. The mechanism of action at a cellular level was assessed by single-cell RNA-sequencing of harvested hearts. Results In vitro anti-FAP CAR-T cells were successfully activated when co-cultured with FAP + target cells. In a dystrophic murine model (D2. mdx ), anti-FAP CAR-T cells, intravenously delivered following lymphodepletion, homed to the heart and skeletal muscles, where they decreased FAP and fibrosis-associated genes. Single-cell RNA-sequencing linked these changes to a decrease in a definite cluster of fibrogenic fibroblasts. Concomitantly, anti-FAP CAR-T cells improved cardiac function compared to control mice injected with GFP-transduced T lymphocytes or bovine serum albumin used as negative controls. Conclusions These results suggest that anti-FAP CAR-T cells could be efficient for mitigating fibrosis and thus complement gene therapy of DMD. More generally, their therapeutic benefits pave the way for potential applications extending to other fibrosis-associated diseases.