Synergistic Antitumor Effect Of CXCL10 With Hyperthermia

IFN-γ-inducible protein 10 (IP-10)/CXCL10 is known to be one of the ELR CXC chemokines, it exhibits no activity on neutrophils while with a potent chemoattractant for T cells, NK cells and monocytes and is an inhibitor of angiogenesis. Although, single therapy with CXCL10 displays some antitumor efficacy in vivo, most data from previous studies suggest that the antiangiogenesis outcome generally improves with adjuvant therapy, such as radiotherapy or chemotherapy. We have previously shown that the combination of CXCL10 with cisplatin led to significant reductions of tumor burden but failed to cure the animals. Due to the multifaceted nature of the angiogenic process in malignant neoplasms, a strategy for antiangiogenic therapy is to design appropriate combination protocols that can counteract the angiogenic factors produced by the tumor and its microenvironment. Recent studies suggested that combination of angiogenesis inhibitor with cytotoxic therapies or other anti- angiogenesis agents may be a possible antitumor strategy.Hyperthermia, one of the oldest documented tumor treatment modalities, is applied as an adjunctive therapy with various established cancer treatments such as chemotherapy, radiotherapy and radiochemotherapy. The initial rational for the use of hyperthermia is based upon a direct tumor cell-killing effect at temperatures above 41-42℃as a function of time. Although the molecular mechanisms of hyperthermia are still under investigation, recent studies indicate that the antitumor effect of hyperthermia is, most likely, not only the result of direct cytotoxicity, but might include other mechanisms.Recently, Cristina Roca et al. have documented that hyperthermia is coupled with an inhibition of angiogenesis through increasing the expression of PAI-1, suggesting that hyperthermia may improve the effectiveness of antiangiogenic drugs. Moreover, studies from other groups have shown that hyperthermia affect not only the immunological reactions of leucocytes but also the immunogeneity of certain tumor cells. These results suggest that hyperthermia may act as an enhancer of gene therapy or immunotherapy. Thus, we wonder whether the combination therapy of CXCL10 with hyperthermia would more efficiently inhibit the growth of tumors.Immunocompetent BALB/c mice bearing Meth A fibrosarcoma were established. Mice were treated with either CXCL10 at 25μg per kg once a day for 20 days, hyperthermia cycled twice (at 42℃for 1h, on day 6 and 12 after the initiation of CXCL10), or together. The results showed that CXCL10 and hyperthermia inhibited the growth of Meth A fibrosarcoma respectively, and interestingly, the combination therapy enhanced the antiangiogenic effects and completely eradicated the established solid tumors. Moreover, the tumor eradicated animals developed a protective T-cell-dependent antitumor memory response against Meth A tumor cells rechallenge. Our result that the combination therapy can achieve a synergistic antitumor could open new perspectives in clinical antitumor therapy.