Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Abstract

SUMMARY Immune checkpoint blockade therapies fail to induce responses in majority of cancer patients; so how to increase the objective response rate becomes an urgent challenge. Here we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin beta receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicates that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.

Immune Checkpoint Blockade and Adaptive Immune Resistance in Cancer

“…This LIGHT-anti-EGFR fusion molecule was able to promote more extensive T cell infiltration into EGFR-expressing tumors. In turn, this prevented resistance to PD-L1 blockade immunotherapy [48]. Similar strategies that target other T cell recruitment factors toward tumors might be feasible.…”

Adoptive immunotherapy via CD4+ versus CD8+ T cells

“…Today, there are a variety of approaches to elicit antitumor immunity. These approaches include therapeutic cancer vaccines (Cherryholmes et al, 2015;Guo et al, 2013;Knutson and Mittendorf, 2015), antitumor antibodies (Antonioli et al, 2016;Meng et al, 2016b), immune checkpoint blockade (Kakavand et al, 2016;Tang et al, 2016), and adoptive T cell therapy (ACT) (Phan-Lai et al, 2015;Restifo et al, 2012;Yee et al, 2002). In this review only ACT will be discussed.…”

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

“…For example, one recent approach reported by Tang et al (6) was to target cancer cells with tumor necrosis factor (TNF) superfamily member LIGHT, a protein ligand that can bind to two different receptors, herpes virus entry mediator (HVEM, also known as tumor necrosis factor receptor superfamily member 14, TNFRSF14), and lymphotoxin beta receptor (LTβR). Targeting LIGHT on cancer cells could overcome tumor resistance to PD-L1 blockade through activating LTβR signaling and recruiting T cell infiltration in tumor microenvironment (6).…”

“…However, only a minority of the total treated patients benefit from the current checkpoint blockade therapy. In other words, resistance to immune checkpoint antibody blockades is commonly observed in most cancer patients (6). There is a great need to better predict the clinical outcome and to overcome the resistance.…”