Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression. A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8 or forkhead box protein 3 (FoxP3) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c- mice and the tumors treated with recombinant IL6 or anti-IL6 antibody. CD8 TILs and CAFs were negatively correlated in intratumoral tissues ( < 0.001), whereas FoxP3 TILs were positively correlated ( < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8 and increased FoxP3 TILs, compared with cancer cells alone. , IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c ( < 0.001) with fewer CD8 TILs than untreated tumors ( < 0.001), whereas no difference in BALB/c- mice. In contrast, FoxP3 TILs increased in IL6-treated tumors ( < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8 TILs in intratumoral tissues. CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. .

Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP + CAFs were strongly associated with lymph node metastasis rather than with other prognostic factors. Furthermore, CAFs affected the ability of esophageal cancer cells to acquire metastatic phenotypes in vitro; this finding was confirmed by data from an in vivo orthotopic metastatic mouse model showing that the number of lymph node metastases increased upon injection of cocultured cancer cells and CAFs. In summary, we verified in vitro and in vivo that the accumulation of CAFs enhances the lymph node metastasis of ESCC. Our data suggest that CAF targeted therapy can reduce lymph node metastasis and improve the prognosis of patients with esophageal cancer in the future.

Enantioselective total synthesis of taxol has been accomplished. Coupling reaction of the optically pure A-ring hydroxy aldehyde with the aromatic C-ring fragment followed by Lewis acid mediated eightmembered B-ring cyclization gave the desired ABC endo-tricarbocycle. The C-ring moiety of this product was reduced under Birch conditions to the cyclohexadiene derivative, which was oxygenated by singlet oxygen from the convex β-face to give the C4β,C7β-diol stereoselectively. For introduction of the C19-methyl, the cyclopropyl ketone was prepared via cyclopropanation of the C-ring allylic alcohol or conjugate addition of a cyano group to the C-ring enone. Reductive cleavage of the cyclopropane ring followed by isomerization of the resulting enol to the corresponding ketone gave the crucial synthetic intermediate containing the C19methyl group. Regioselective transformation of three hydroxyl groups of this intermediate, conversion of the C4-carbonyl group to the allyl chloride, and introduction of the C10-oxygen functionality afforded a precursor for D-ring construction. Dihydroxylation of the allyl chloride moiety followed by basic treatment of the resulting diol gave a fully functionalized taxol skeleton. Functional group manipulation of this product including attachment of the C13 side chain provided (-)-taxol.

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