3.4.2 Tumor vaccines
Tumor vaccines, as a form of active immunotherapy, work by providing tumor-associated antigens and activation signals to stimulate endogenous tumor-specific T cells[75]. If a vaccine can turn ovarian cancer into an immunogenic hot tumor, that is generating a lot of tumor-specific immune cells, then checkpoint inhibitors may produce a better response rate in combination therapy[76]. There is a challenge for cancer vaccines, to identify the appropriate immune adjuvant that has an ability of non-antigenic molecules[77] to induce robust immune responses for the efficacy of vaccines for cancer[78].
Statins should be viewed as a rational vaccine adjuvant. Xia Y et al. report that lipophilic statin inhibits the geranylgeranylation of small GTPases, such as Rab5 in antigen-presenting cells (APC), inducing both Th1 and cytolytic T cell responses, which of effect are scarce in clinical adjuvants. It also can delay endosomal antigen entry into degradative lysosomes, that is manipulation of endocytic maturation without overt inflammatory signals, thus enhancing antigen presentation[11]. Furthermore, statins have been established to make myeloid cells sensitive to external stimuli like lipopolysaccharide (LPS) and to produce cytokines, and it with IL-2 co-stimulation also activate human NK cells[78]. A study in clinic is reported that simvastatin treatment induces autoantibodies against oxLDL increasing, with an expansion of CD8+ T cells found[79]. This means that statins may be used as an adjuvant in tumor vaccines to melt the “coldness” of ovarian cancer by increasing infiltration by CD8+ T cells, providing a new view of combination therapy.
Outlook
At present, a mass of clinical studies and experiments have confirmed the anti-cancer effect of statins in OC. According to the results of many mechanism studies, it can be inferred that statins still have great potential in the field of anti-OC, but due to the limitations of indications of statins usage and routine treatment regimen in clinic for clinical trial design, prospective studies are still few. In this review, we found that there are relatively many studies on the combination of statins with paclitaxel and platinum drugs, while studies on the combination of statins with such promising drugs like bevacizumab, PARP is, anti-PD/PD-1 and tumor vaccines in the treatment of ovarian cancer are scarce. In Figures 1, we summarize the systematic connection of mechanisms about statins associating with treatment of EOC. Meanwhile, it is also critical to study how to increase the concentration of statins in the ovaries, rather than the plasma concentration, for practical application and efficacy. With researches deepened on statins in the fields of immunotherapy and other fields, statins have shown a surprising side, which suggests the necessity of conducting experimental studies on the combination of statins with the medicines above to provide evidence and confidence for clinical trials, so as to look forward to entering the clinical trial stage as soon as possible.
Conflicts of interest
This work was supported by the Shaanxi Provincial Health Commission[S2020-YF-YBSF-0315];Xi ’an Health Commission [2023yb03]