Targeted in vivo expression of IFN-γ-inducible protein 10 induces specific antitumor activity

Abstract

Although it is known that the chemoattractant effect of IFN-gamma inducible protein 10 (IP-10), a CXC chemokine (CXCL10), plays an important role in T cell-mediated antitumor immunity in vivo, whether IP-10 is involved in modulating the proliferation, survival and functional activation of tumor-specific T cells remains poorly investigated. Using an experimental mouse tumor model, we demonstrated that the in vivo growth of 4T1 tumor cells harboring IP-10 gene (4T1-IP-10) was inhibited. Mice inoculated with 4T1-IP-10 tumor cells expressing functional IP-10 survived over 90 days, whereas mice injected with control parental 4T1 cells and mice of control 4T1 cells transduced with control plasmid all succumbed to the tumor by day 38 after tumor inoculation. Mechanical analysis showed that targeted expression of IP-10 in 4T1 tumor cells markedly enhanced the infiltration of tumor-specific T cells into the 4T1-IP-10 tumor. These tumor infiltrating T lymphocytes (TILs) recruited by IP-10 were potent cytolytic killers against 4T1 tumor cells and were able to proliferate and produce high levels of IFN-gamma in response to 4T1 cells. In vivo administration of IP-10-recruited TILs induced vigorous proliferation of these TILs in situ in the 4T1-IP-10 tumor but not in the 4T1-pcDNA3 and parental 4T1 tumors. Furthermore, culture of TILs together with recombinant IP-10 significantly enhanced the proliferation and expansion of IP-10-recruited TILs in response to 4T1 tumor antigens. These results suggest that IP-10 is not only able to chemoattract tumor-specific T cells into the local tissue, but also enhance the proliferation, survival, and functional activation of these TILs, leading to the tumor regression. Thus, targeted expression of IP-10 in vivo will allow for the development of a novel approach for immunotherapy of tumor.