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

Abstract

LIGHT, a ligand for the lymphotoxin-β receptor, establishes lymphoid-like tissues inside tumor sites and recruits naïve 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 IFNγ 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. ©2010 AACR.

Trafficking of T Cells into Tumors

“…Interestingly, it has been reported that LIGHT, a TNF superfamily member and a ligand for the lymphotoxin b receptor, facilitates the generation of TLS (39,40) and recruits na€ ve T cells into the tumor (41). Expression of LIGHT in tumors has been shown to enhance chemokine secretion within the tumor, favoring the infiltration and expansion of functional CD8 þ T cells (42). However, it remains unclear what role TLS plays in the LIGHT-mediated T-cell recruitment to tumor.…”

LTβR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8+T cells

“…Our study focuses on the role of DCintrinsic LTβR signaling in provoking a CD8 + T-cell response to cell-associated Ag, and this may have functional significance to help-dependent situations such as tumor eradication and graft rejections, scenarios where LTβR signaling has been implicated (10)(11)(12)41). The evaluation of LTβR signaling in DCs during autoimmunity remains to be fully elucidated and would provide therapeutic insight into the potential value of LTβR inhibition for treatment of such chronic diseases.…”

Molecular diagnosis of a laboratory mouse papillomavirus (MusPV)

“…PVs are non-enveloped small DNA viruses that are highly species-specific, most of which are anatomic site restricted. The species-specificity of HPVs has hindered the development of mouse models, other than transgenic mice, that can reveal clues about HPV carcinogenesis (Campo, 2002;Borzacchiello et al, 2009;Gissmann and Nieto, 2009;Eckert et al, 2000;Stelzer et al, 2010;Kanodia et al, 2010). Other than MusPV Joh et al, 2011), the only PV associated with any mouse species is MmiPV1, isolated from a zoo colony of European harvest mice (Bernard et al, 2010;Sundberg et al, 1996).…”