Expression of LIGHT/TNFSF14 Combined with Vaccination against Human Papillomavirus Type 16 E7 Induces Significant Tumor Regression

LIGHT, a ligand for the lymphotoxin-beta receptor, establishes lymphoid-like tissues inside tumor sites and recruits naive T cells into the tumor. However, whether these infiltrating T cells are specific for tumor antigens is not known. We hypothesized that therapy with LIGHT can expand functional tumor-specific CD8(+) T cells that can be boosted using HPV16E6E7-Venezuelan equine encephalitis virus replicon particles (HPV16-VRP) and that this combined therapy can eradicate human papillomavirus 16 (HPV16)-induced tumors. Our data show that forced expression of LIGHT in tumors results in an increase in expression of IFN gamma and chemoattractant cytokines such as interleukin-1a, MIG, and macrophage inflammatory protein-2 within the tumor and that this tumor microenvironment correlates with an increase in frequency of tumor-infiltrating CD8(+) T cells. Forced expression of LIGHT also results in the expansion of functional T cells that recognize multiple tumor antigens, including HPV16 E7, and these T cells prevent the outgrowth of tumors on secondary challenge. Subsequent boosting of E7-specific T cells by vaccination with HPV16-VRP significantly increases their frequency in both the periphery and the tumor and leads to the eradication of large well-established tumors, for which either treatment alone is not successful. These data establish the safety of Ad-LIGHT as a therapeutic intervention in preclinical studies and suggest that patients with HPV16(+) tumors may benefit from combined immunotherapy with LIGHT and antigen-specific vaccination. Cancer Res; 70(10); 3955-64. (C) 2010 AACR.