Abstract

Tumor escape from immunologically mediated destruction is a well-studied phenomena and has been shown to utilize several pathways in common with physiological conditions such as pregnancy, as well as ocular or testicular immune privilege. Recent interest in senescence has revealed that senescent cells surrounding tumors contribute to development of a specific microenvironment that may allow for immune escape. Senescent cells have been reported to possess a “senescence associated secretory phenotype” (SASP) which produces inflammatory agents that directly and indirectly contribute to suppression of T cell and NK cell function. Exosomes secreted by senescent cells can suppress T cell activation, as well as downregulate activity of dendritic cells, which are needed for initiation of immunity. Studies have demonstrated that reduction of senescent cell load increases tumor sensitivity to a variety of therapies. We will overview supportive evidence for use of senolytics to potentiate the efficacy of immunotherapy in cancer, as well as discuss our preliminary findings regarding use of SenoVax™ (IND #30745), an autologous, polyvalent dendritic cell senolytic vaccine being developed for treatment of advanced non-small cell lung cancer.

Keywords

immune tolerance, cellular senescence, immunotherapy resistance, senolytics, T cell activation, NK cell function, tumor-associated immune suppression, senescence surveillance.