LIGHT May Improve Immune Checkpoint Blockade Response

A protein that recruits tumor-infiltrating lymphocytes has the potential to improve response rates to immune checkpoint blockade, a recent study suggests. The researchers demonstrate that having insufficient T cells inside tumors explains why many patients do not respond to immunotherapy.

Researchers have long suspected that significant T-cell infiltration of patients' tumors is necessary for response to PD-L1 blockade, but the theory is difficult to confirm clinically and had never been proven in animal models. In this study, investigators developed mouse models of PD-L1–expressing tumors, both with and without significant T-cell infiltration. An analysis of the tumor tissue revealed that tumors with significant T-cell infiltration were well controlled by PD-L1 inhibitors, whereas those with few T cells were unresponsive.

“We've shown that sufficient T-cell infiltration, not necessarily PD-L1 expression, determines response to PD-L1 blockade,” says the study's senior investigator Yang-Xin Fu, PhD, professor of pathology and immunology at The University of Texas Southwestern Medical Center in Dallas. The results are published in Cancer Cell.

Fu's team set out to discover whether increasing T-cell infiltration of tumors could overcome resistance to PD-L1 blockade. The researchers had previously shown in the lab that upregulation of the costimulatory molecule LIGHT, a tumor necrosis factor (TNF) superfamily member, in established tumors triggers production of chemokines that recruit high numbers of T cells to the tumor microenvironment, leading to tumor regression.

In this study, they tested the strategy in mice by attaching an EGFR antibody to LIGHT to target EGFR-expressing tumors with low T-cell infiltration. They found that anti-EGFR–guided LIGHT led to tumor regression in the mice whereas anti–PD-L1 therapy alone had no effect. However, neither PD-L1 inhibitors nor LIGHT, individually, were sufficient to control large tumors, possibly because LIGHT also increased the level of PD-L1 expression. As a result, combining PD-L1 blockade with LIGHT may be the most effective treatment strategy, the researchers concluded.

“Our data suggest that combining treatments that inhibit PD-L1 expression while increasing T-cell infiltration of tumors can overcome resistance to checkpoint blockade,” says Fu. “LIGHT appears to allow tumors to regain their ability to respond to checkpoint blockade.”

The combination of PD-L1 inhibitors and anti–CTLA-4 is currently the most promising strategy being tested to increase the response rate to checkpoint blockade, Fu notes. However, anti–CTLA-4 also appears to work best when tumors have preexisting T-cell infiltration, suggesting that it may be more effective in combination with LIGHT than with another checkpoint inhibitor. However, this theory has not yet been tested, adds Fu.

The findings lay the foundation for developing multiple novel classes of antibody-based drugs, notes Timothy A. Chan, MD, PhD, vice chair of radiation oncology and director of the Translational Oncology Division at Memorial Sloan Kettering Cancer Center in New York, NY. EGFR, as well as HER2, are strong candidates for antibodies because they are overexpressed in some human cancers.

“This may lead to strategies to make HER2-positive breast cancer more immunogenic,” says Chan. “Using LIGHT may be one way to convert nonimmunogenic, anti–PD1-refractory tumors into responsive ones.”

However, he adds, because the current study was conducted in mice, “it still remains to be seen whether LIGHT will work in humans.” –Janet Colwell