Targeting tumors with LIGHT to generate metastasis-clearing immunity

Abstract

Metastatic diseases cause the majority of morbidity and mortality of cancer patients. Established tumors form both physical and immunological barriers to limit immune detection and destruction. Current immunotherapy of vaccination and adoptive transfer shows limited effect at least in part due to the existing barriers in the tumors and depending on the knowledge of tumor antigens. Tumor necrosis factor (TNF) superfamily (TNFSF) member 14 (TNFSF14) LIGHT interacts with stromal cells, dendritic cells (DCs), NK cells, naïve and activated T cells and tumor cells inside the tumor tissues via its two functional receptors, HVEM and lymphotoxin beta receptor (LTbetaR). Targeting tumor tissues with LIGHT leads to augmentation of priming, recruitment, and retention of effector cells at tumor sites, directly or indirectly, to induce strong anti-tumor immunity to inhibit the growth of primary tumors as well as eradicate metastases. Intratumor treatment would break tumor barriers and allow strong immunity against various tumors without defining tumor antigens. This review summarizes recent findings to support that LIGHT is a promising candidate for an effective cancer immunotherapy.

Figure 1. LIGHT enhances priming of anti-tumor T cells

Membrane-bound LIGHT stimulates stromal cells via LTβR to upregulate chemokines, such as SLC, and adhesion molecules to recruit naïve T cells and DCs into the tumor tissue. LIGHT promotes the survival, expansion and maturation of DCs, which possibly prime the T cells in situ. LIGHT also costimulates recruited naïve T cells, possibly through HVEM, in the present of tumor antigen for their activation and expansion. NK cells, which express HVEM, can be activated by LIGHT to produce IFN-γ to facilitate the expansion and differentiation of T cells and production of abundance of IFN-γ. Tumor cells signaled by LIGHT via LTβR and/or HVEM may become apoptotic in the presence of IFN-γ leading to antigen release and better priming of anti-tumor immunity.

Figure 2. LIGHT recruits and promotes effector T cells inside the tumor tissue

Membrane-bound LIGHT stimulates stromal cells via LTβR to upregulate chemokines, such as IP-10 and Mig to recruit activated T cells into the tumor tissue. LIGHT may also stimulate the coming T cells for their further activation and expansion. NK cells activated by LIGHT through HVEM produce IFN-γ to facilitate the expansion, differentiation and production of more abundance of IFN-γ by T cells. IFN-γ in turn promotes the production of IP-10 and Mig to form a positive loop to recruit and promote effector T cells in the tumor tissue. The functional tumor antigen-specific T cells from LIGHT-mediated environment may traffic systemically for eradication of metastases.