Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regressionof established tumors immortalized by HPV-16

Two recombinant Listeria monocytogenes (rLm) strains were produced that sec rete the human papilloma virus-16 (HPV-16) E7 protein expressed in HPV-16-a ssociated cervical cancer cells. One, Lm-E7, expresses and secretes E7 prot ein, whereas a second, Lm-LLO-E7, secretes E7 as a fusion protein joined to a nonhemolytic listeriolysin O (LLO). Lm-LLO-E7, but not Lm-E7, induces th e regression of the E7-expressing tumor, TC-1, established in syngeneic C57 BL/6 mice. Both recombinant E7-expressing rLm vaccines induce measurable an ti-E7 CTL responses that stain positively for H-2D(b) E7 tetramers. Depleti on of the CD8(+) T cell subset before treatment abrogates the ability of Lm -LLO-E7 to impact on tumor growth. In addition, the rLm strains induce mark edly different CD4(+) T cell subsets. Depletion of the CD4(+) T cell subset considerably reduces the ability of Lm-LLO-E7 to eliminate established TC- 1 tumors. Surprisingly, the reverse is the case for Lm-E7, which becomes an effective anti-tumor immunotherapeutic in mice lacking this T cell subset. Ab-mediated depletion of TGF-beta and CD25(+) cells improves the effective ness of Lm-E7 treatment, suggesting that TGF-beta and CD25(+) cells are in part responsible for this suppressive response. CD4(+) T cells from mice im munized with Lm-E7 are capable of suppressing the ability of Lm-LLO-E7 to i nduce the regression of TC-1 when transferred to tumor-bearing mice. These studies demonstrate the complexity of L monocytogenes-mediated tumor immuno therapy targeting the human tumor Ag, HPV-16 E7.