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Development of immunotherapy, especially checkpoint inhibitors, dramatically improved the prognosis of some malignancies. However, problems on the occurrence of severe adverse effects and limited responses to these checkpoint inhibitors remain. Recently, tumor infiltrating lymphocytes(TILs)are the predictive markers of immunotherapies based on clinical evidence. The proportion of cytotoxic T cells in the tumor has been reported to affect the antitumor effect. TILs in the tumor are thought to be controlled by the interaction between cancer and tumor microenvironment. As a cause of tumor immunosuppression, cancer-associated fibroblasts(CAFs)play the main role in the tumor microenvironment. We considered the strong involvement of tumor microenvironment, particularly the role of CAFs, and reported the interaction between CAFs and proliferation, invasion, angiogenesis, and resistance in the conventional therapy. The correlation between CAFs and tumor immunity and the immunosuppression promoted by CAFs were also evaluated. Their effects will be reported in our future studies.

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

Background & Aims: Esophageal squamous cell carcinoma (ESCC) is known to be a highly angiogenic tumor. Here, we investigated the role of the stromal fibroblasts in the ESCC-induced angiogenic response using a novel 3-dimensional model., Methods: A novel assay was developed where cocultures of ESCC and esophageal fibroblasts induced human microvascular endothelial cell (HMVEC) vascular network formation in a 3-dimensional collagen gel. Biochemical studies showed that the ESCC-induced activation of the fibroblasts was required to induce vascular network formation via a transforming growth factor (TGF)-beta and vascular endothelial growth factor (VEGF)-dependent pathway., Results: Conditioned media from a panel of 4 ESCC lines transdifferentiated normal esophageal fibroblasts into myofibroblasts via TGF-beta signaling. The presence of fibroblasts was essential for efficient HMVEC network formation, and the addition of ESCC cells to these cultures greatly enhanced the angiogenic process. The role of TGF-beta in this process was shown by the complete inhibition of network formation following TGF-beta inhibitor treatment. Finally, we showed that ESCC-derived TGF-beta regulates angiogenesis through the release of VEGF from the fibroblasts and that the VEGF release was blocked following TGF-beta inhibition., Conclusions: This study shows the essential role of fibroblasts in the ESCC angiogenic-induced response and suggests that the pharmacologic targeting of the TGF-beta signaling axis could be of therapeutic benefit in this deadly disease.

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity. [ABSTRACT FROM AUTHOR]

Simple Summary: In esophageal cancer, the 5-year survival rate for patients who underwent esophagectomy with chemoradiotherapy is poor, with an estimated rate of 32.4%. One reason for this outcome is the low response rate to preoperative chemotherapy or radiotherapy. In this study, we revealed that low-dose chemotherapy or radiotherapy causes malignant phenotypic changes, such as cancer-associated fibroblasts, in normal fibroblasts. Furthermore, radiotherapy-resistant fibroblasts significantly increased the total number of tumors in the peritoneal cavity compared to the control group in peritoneal-disseminated tumor models. Thus, conventional cancer therapy has anti-therapeutic effects via activation of fibroblasts, and it is important to determine which modality of esophageal cancer treatment is selected or combined, recognizing that inappropriate radiotherapy and chemotherapy can lead to tumor resistance. Esophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP+ CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future. [ABSTRACT FROM AUTHOR]

Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) and its clinical significance remains unclear. Herein, we systematically analyzed a large cohort of 627 colorectal cancer (CRC) specimens, and investigated the expression pattern of ADAR1 and its biological significance on the antizyme inhibitor 1 (AZIN1) RNA editing levels. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues vs. normal mucosa, and these findings correlated with the increased expression of mesenchymal markers, Vimentin (ρ = 0.44) and Fibroblast activation protein (ρ = 0.38). Intriguingly, ADAR1 expression was specifically upregulated in both cancer cells and fibroblasts from cancerous lesions. Conditioned medium from cancer cells led to induction of ADAR1 expression and activation of AZIN1 RNA editing in fibroblasts (p < 0.05). Additionally, edited AZIN1 enhanced the invasive potential of fibroblasts. In conclusion, we provide novel evidence that hyper-editing of AZIN1 enhances the invasive potential of CAFs within the TME in colon and is an important predictor of tumor invasiveness in CRC. [ABSTRACT FROM AUTHOR]