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

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Haidong Tang, Yang Wang, Lukasz K. Chlewicki, Yuan Zhang, Jingya Guo, Wei Liang, Jieyi Wang, Xiaoxiao Wang, Yang-Xin Fu
Immune checkpoint blockade therapies fail to induce responses in the 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 β-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 indicate that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.

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Teaser

Tang et al. show that sufficient T cell infiltration in tumors is critical for the response to PD-L1 blockade and that treating EGFR⁺ resistant tumors with a fusion protein containing TNF superfamily member LIGHT with anti-EGFR antibody can increase tumor infiltrating T cells and overcome the resistance to checkpoint therapy.


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