Interferon ?-induced intratumoral expression of CXCL9 alters the local distribution of T cells following immunotherapy with Listeria monocytogenes.

ABSTRACT: The ability of Listeria monocytogenes-based anticancer vaccines to induce tumor regression depends on the responsiveness of malignant cells to interferon ? (IFN?). Inhibition of IFN? limits the recruitment of T cells to the tumors of vaccinated mice. We hypothesized that vaccination with immunotherapeutic L. monocytogenes induces the IFN?-dependent production of chemokines that regulate the migration of tumor-infiltrating T cells. To gain further insights into this issue, we examined the chemokine responses of a transplantable, human papillomavirus (HPV)-immortalized murine tumor model (TC-1) following the administration of a L. monocytogenes-based immunotherapeutic agent that expresses E7 from HPV-16. Here, we report that the administration of L. monocytogenes-based anticancer vaccines increases the secretion of chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL10 by tumors, hence favoring the recruitment of T cells bearing the cognate chemokine (C-X-C motif) receptor 3 (CXCR3). Furthermore, the expression of CXCL9, but not CXCL10, in TC-1 tumors was significantly reduced upon anti-IFN? antibody treatment. CXCL9 was highly expressed by TC-1 cells following the administration of IFN? and tumor necrosis factor ? (TNF?), in vitro. Moreover, the inhibition of CXCL9 in TC-1 cells reduced the proportion of CD8⁺ T cells infiltrating tumors in vaccinated mice, while increasing that of CD4⁺ T cells, thus altering T-cell subset distribution. We conclude that the administration of L. monocytogenes-based anticancer vaccines regulates T_H1 chemokine responses and that malignant cells are an important source of these chemokines.

SUBMITTER: Guirnalda P 

PROVIDER: S-EPMC3782529 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature