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

The ability of Listeria monocytogenes-based anticancer vaccines to induce tumor regression depends on the responsiveness of malignant cells to interferon gamma (IFN gamma). Inhibition of IFN gamma limits the recruitment of T cells to the tumors of vaccinated mice. We hypothesized that vaccination with immunotherapeutic L. monocytogenes induces the IFN gamma-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 tumor cells, 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 gamma antibody treatment. CXCL9 was highly expressed by TC-1 cells following the administration of IFN gamma and tumor necrosis factor alpha (TNF alpha), 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(H)1 chemokine responses and that malignant cells are an important source of these chemokines.