Reduction of solid tumors by senescent cell immunization.

backgroundImmunologically mediated clearance of senescent cells has been demonstrated in several model systems. Given increasing evidence for these cells promoting tumor pathology and immune escape, we sought to examine whether a vaccine against senescent cells can lead to tumor regression. MATERIALS AND

methodsA senolytic dendritic cell (DC) immunotherapy (“SenoVax™”) was created by pulsing DCs with lysate from in vitro generated syngeneic senescent fibroblasts. Prophylactic and therapeutic activity of SenoVax on tumor growth and metastasis was assessed in the Lewis Lung Carcinoma (LLC) model. The immunogenicity of SenoVax™ was measured using cytotoxicity, proliferation, and cytokine assays. Adoptive transfer of lymphocytes from vaccinated mice into naïve mice was performed in a prophylactic tumor challenge model. Assessment of plasma senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 was performed by ELISA. Synergy of SenoVax™ with immune checkpoint inhibitors and the universality of the vaccine’s effects against other tumors was assessed. Furthermore, induction of autoimmunity was assessed by complement activation and autoantibody formation.

resultsSenoVax™ was created by pulsing DC with cell lysate from senescent fibroblasts, producing DCs that expressed co-stimulatory molecules, stimulated T cell proliferation, and expressed the senescence antigen p16. SenoVax™ induced prophylactic and therapeutic tumor regression in LLC primary and metastatic murine tumor models. T cell proliferative and cytokine recall responses towards senescent cells but not to control stromal cell pulsed DCs were detected in vaccinated mice. Additionally, reduction in senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 were observed. Adoptive transfer experiments revealed a role for CD8+ T cells in transplanting protection. When SenoVax™ was administered in combination with anti-PD-L1 or anti-CTLA-4 antibodies, the data showed synergistic effects in reducing tumor growth. SenoVax™ also demonstrated reduction of GL281 glioma, Pan01 pancreatic cancer, and 4T1 breast cancer cell growth. No significant activation of complement or induction of autoantibodies was observed.

conclusionVaccination with DC pulsed senescent cells resulted in reduction of tumor growth in a CD8+ T cell and interferon gamma-associated manner in lung cancer as well as other tumor models. The data provide mechanistic support for advancement of senolytic immunotherapy as a novel form of cancer therapy.