Abstract
Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.
Highlights
Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment
The main types of these tumors are esophageal, pancreatic and scirrhous-type gastric cancers, which are cancer types composed of an abundant organized stroma, and the mechanisms of resistance to conventional treatment for such stroma-rich tumors could be as follows: first is therapeutic resistance acquired via the interaction between cancer and stromal cells, second is a reduction in drug delivery efficiency due to an increase in stromal interstitial pressure, and third is promotion of the secretion of cancer-promoting substances by CAFs during DNA-damaging treatment
We demonstrated that esophageal cancer (EC) cells originating from squamous cell carcinoma or adenocarcinoma could stimulate fibroblasts into the CAF phenotype, which is the main fibroblast phenotype in the tumor stroma, and we suggested that these CAFs influenced cancer cells to develop more malignant phenotypes, which could be related to therapeutic resistance
Summary
Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Stromal cells are strongly involved in the progression of cancer cells, and among stromal cells, cancer-associated fibroblasts (CAFs) have been reported to have an important role in the tumor microenvironment. Overcoming therapeutic resistance is one of the challenges in our efforts, and the development of novel therapeutic approaches is needed to improve the prognosis of EC patients
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