IL-12 therapy suppresses TC-1 tumor growth accelerated by admixture of the docetaxel-treated senescent tumor cells

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Cellular senescence is considered to be a principal barrier against tumorigenesis that inhibits acquisition of an immortal phenotype. Tumor cell senescence can be induced by antitumor therapy, such as irradiation or chemotherapy and, under certain circumstances, also by cytokines (IFNγ and TNFα). Senescent cells do not proliferate, though, they can survive in the organism for a long time and influence tumor development. Senescent cells express a number of secreted proteins and growth factors that may stimulate or inhibit cell proliferation. We can hypothesize that not only senescence induction but also subsequent senescent cells elimination can be critical for effective antitumor therapy. In this study, we evaluated the impact of docetaxel in terms of senescence induction, using two C57BL/6 mice-derived tumor cell lines TC-1 and TRAMP-C2. We have demonstrated acceleration of tumor growth, when proliferating TC-1 tumor cells were co-administered into syngeneic mice together with tumor cells that had been subjected to the senescence-inducing treatments with docetaxel. After this treatment, both TC-1 and TRAMP-C2 cells were alive but senescent, as characterized by specific cell morphology, increased SA-β-galactosidase activity, increased expression of p16 and p21 CDK inhibitors, as well as of the DNA damage marker γH2AX. Proliferating cell cultures and senescent cell cultures contained >80% proliferating and <2% senescence-associated, β-galactosidase positive cells, DTX-treated (senescent) cell cultures contained <2% proliferating cells and <70% senescence-associated, β-galactosidase positive cells, respectively. Secretome analysis of the senescent revealed increased expression of a number of inflammatory and protumorigenic cytokines and chemokines. We have hypothesized that immunotherapy with IL-12 could be effective against both senescent and presenescent tumor cells by induction of both specific and non-specific immune responses and thereby should inhibit the growth of the senescence-accelerated tumor cells. This accelerated tumor growth was effectively inhibited by cell therapy using irradiated IL-12-producing tumor cells. We established that immunotherapy, such as the IL-12 treatment, can serve as an effective tool for elimination of the detrimental effects caused by senescent tumor cells.

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