CHPs enable precise detection of ECM depletion in solid tumors, offering researchers critical insights into how stromal-targeted therapies improve T cell infiltration and immunotherapy efficacy in PDAC.
While chimeric antigen T (CAR-T) cells have shown immense promise as a cancer therapeutic, they have limited efficacy in treating solid tumors. This is due to immune exclusion, whereby physical barriers such as stromal cells woven into dense extracellular matrices prevent anti-cancer immune cells from reaching the tumor. This group of researchers hypothesized that CAR-T cells which target fibroblast activation protein (FAP) may enable T cells to overcome these barriers through selectively eliminating FAP+ fibroblasts. This effect would allow for T cells and other immune cells to actually reach the tumor and work to limit tumor growth.
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In this paper, researchers show that treating tumors with anti-FAP CAR T cells leads to reduction of tumor-associated fibroblasts as seen by reduced expression of FAP, 𝛼-SMA, PDGFR-𝛼, and PDPN, 2 weeks post-treatment compared to MigR vector-transduced control T cells. Since fibroblasts are the main producers of the extracellular matrix in tumors, this group used collagen hybridizing peptides (CHP) to measure collagen following treatment with FAP-CAR T. Using biotinylated CHP (B-CHP), they showed reduction of tumor-associated collagens which correlated to lower levels of fibronectin, another extracellular matrix (ECM) protein, as detected by immunofluorescent antibody staining.
As a result of fibroblast and ECM depletion, FAP-CAR T treatment promoted invasion and penetration of T cells while maintaining their functionality. Therefore, while tumor-antigen targeted CAR-T therapies and PD-1 blockade were each ineffective alone at treating solid tumors, combination therapy with FAP-CAR T exposed the tumor to these powerful immunotherapies. As a result, this paper achieved delayed tumor growth in both autochthonous and patient derived xenograft models of pancreatic ductal adenocarcinoma (PDAC) using these therapies following pretreatment with the FAP-CAR T.
