Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br the efficacy of therapies targeting FAPa it is necessary

    2019-10-02

    
    the efficacy of therapies targeting FAPa, it is necessary to delay the treatment time until after tumor establishment in mice to mimic real clinical cases (Fig. 4D). In this model, the anti-tumor effect of CpVR-FAP, a DNA vaccine targeting FAPa constructed in our previous work [26], almost completely disappeared (Fig. 4E). Recent studies have shown that full-length FAPa with the S624A mutation still promotes tumor growth via non-enzymatic activity [27], and a specific transmembrane region plays a crucial role in the dimerization and activity of FAPa [28]. These previous studies indicate that vaccines containing full-length FAPa have safety issues. Furthermore, the immunogenicity of vaccines needs to be improved. tPA signal sequences have the capacity to elicit cell-mediated and humoral immune responses in vaccinated animals and are used extensively in the construction of viral and DNA vec-tor vaccines. To enhance the safety and efficacy of the vaccine, we constructed a new FAPa-targeted vaccine [shF(m)] that only con-tains the extracellular domain of human FAPa (amino acids 27–
    760) and a tPA signal sequence fused to the N-terminal region. shF(m) induced more FAPa-specific CTLs than hF(m) (CpVR-
    FAP), which are crucial for the therapeutic efficacy of tumor vac-cines. The isolated splenocytes from the shF(m) group could secrete more IL-2 in vitro and the relative expression levels of IL-2 and GzmB were up-regulated. Furthermore, the vaccine over-came the immunosuppressive environment, facilitated an increase
    in CD8+ T cell infiltration in an established 4T1 tumor model, and induced a shift in local immunity from Th2 to Th1, which is more conducive to tumor destruction [10]. To compare the anti-tumor effects of human and mouse FAPa vaccines on mouse mammary gland models, a DNA vaccine expressing full-length mouse FAPa, mF(m), was constructed (Fig. 1A). The results (Figs. 1 and 3B, C) showed that hF(m) and mF(m) had similar intensities with respect to immunogenicity and the inhibition of tumor growth. Further-more, human FAPa could stimulate human peripheral blood mononuclear Relebactam to produce FAPa-specific T cells, which proves that a human FAPa vaccine could be used for human cancer immunotherapy [25]. Among the vaccines examined, shF(m) had the strongest anti-tumor activity and was most suitable for the clinical treatment of human cancers.
    Tumors escape from Relebactam surveillance and elimination by the immune system by a variety of complementary immunosuppres-sive mechanisms, such as the downregulation of MHCI, upregula-tion of surface immunosuppressive ligands (e.g., PDL-1), increases in the expression of immunosuppressive factors (e.g., IL-10, TGF-b), and recruitment of various immunosuppressive cells (e.g., Tregs, MDSCs) into the TME [1–4]. CAFs could promote the recruitment and function of MDSCs via the secretion of CCL2 and SDF-1 (CXCL12) and inhibit the function of effector T cells via the secretion of TGF-b [14–16,46]. The FAPa-targeted vaccine shF(m) effectively decreased the number of FAPa+ CAFs in the TME, reduc-ing the expression of CCL2 and CXCL12, thereby decreasing the infiltration of MDSCs. The expression levels of factors related to immunosuppression in the TME were also weakened. Accordingly, 
    targeting FAPa+ CAFs may relieve immunosuppression and ECM barrier function in the TME [9,10,17].
    Furthermore, we developed a codon-optimized shF(m) frag-ment, OshF(m), with similar inhibitory effects on tumor growth and improvements in mouse survival to those of shF(m), but more effective removal CAFs and immunosuppressive molecules in the TME, which may improve the outcomes of immunotherapy and chemotherapy [32,34,35,42]. Moreover, the nucleotide sequence of the OshF(m) fragment had only 76% homology with the original sequence, which is convenient for detecting the distribution of the vaccine in the human body in future clinical applications.
    Interestingly, despite the OshF(m) vaccine enhancing anti-tumor T cell immune responses and reducing the number of CAFs in the TME, this did not significantly prolong the survival time of mice. This may be due to that all vaccines mentioned in this article targeted only at one single antigen (FAPa), which made the immune responses induced by the vaccines only act on FAPa+ CAFs. Even though OshF(m) could regulate the TME, there is still a lack of treatment for cancer cells. Previous studies have shown that a cancer cell vaccine expressing FAPa can target both cancer cells and FAPa+ CAFs, and significantly prolong the survival time of mice compared with single cancer cell vaccine [42]. Therefore, OshF(m) might have a better therapeutic effects if it was combined with other vaccines targeting cancer cells.