Understanding Resistance to Cancer Immunotherapy

Patients with advanced melanoma who produce even a slight immune reaction to their disease—in the form of tumor-infiltrating T cells—are far more likely to respond to checkpoint inhibitors like ipilimumab (Yervoy; Bristol-Myers Squibb) and pembrolizumab (Keytruda; Merck). A recent study from the University of Chicago, IL, pinpoints a molecular mechanism underlying the absence of this antitumor immunity, which strongly correlates with Wnt/β-catenin pathway activity.

The researchers analyzed two groups of metastatic human melanoma samples, 91 lacking T-cell invasion and inflammation, and 106 with beneficial T cell–led inflammation. Nearly half (48%) of the noninflamed subset had high β-catenin activity, compared to just 4% in the inflamed subset. The team then engineered two mouse models of BRAF V600E–mutant melanoma: one with and one without active β-catenin. In the former, they observed that T cells were excluded from the tumor microenvironment, along with a rare subset of CD103+ dendritic cells, known to be crucial for T-cell activation.

Next, the researchers figured out why CD103+ dendritic cells were absent in tumors with β-catenin activity. “Normally, these cells are attracted by a chemokine called CCL4, which tumors produce,” explains immunologist Thomas Gajewski, MD, PhD, the study's senior author. “However, we found that active β-catenin suppresses CCL4′s production, in part by inducing expression of ATF3, a transcriptional repressor that turns off the CCL4 promoter.”

Essentially, tumor-intrinsic β-catenin signaling is a key culprit in the defective recruitment of CD103+ dendritic cells, which in turn keeps T cells from accessing tumors, making immunotherapy ineffective.

When T cell–inflamed mice lacking β-catenin were given a combination of anti–CTLA-4 and anti–PD-L1 monoclonal antibodies, tumor growth was significantly hampered. In contrast, no therapeutic effects were seen in mice with active β-catenin until CD103+ dendritic cells were injected directly into their tumors.

“This dendritic cell subset seems to be the fulcrum, without which the ability to mount a host immune response falls apart,” Gajewski notes.

“It will be very interesting to see if this molecular mechanism is dominant or restricted to certain melanomas, and how it relates to other potential causes of immune cell exclusion,” says Antoni Ribas, MD, PhD, director of the tumor immunology program at the University of California, Los Angeles, who was not involved in the study.

Gajewski and his group are now pursuing drugs that target Wnt/β-catenin signaling. “We'd only need to interfere with the immunologically relevant points of this pathway,” he says. “For instance, a drug could target ATF3 without touching β-catenin itself, which might be too toxic.” Additionally, having found that focused high-dose radiation can activate CD103+ dendritic cells in melanoma, they plan to combine this tactic with anti–PD-1 drugs in another study. They also have evidence that germline polymorphisms in immune regulatory genes and differences in intestinal microbiota influence the strength of host antitumor immunity.

“Instead of lab observations that get moved into the clinic, patients have become our discovery platform,” Gajewski remarks. “This approach of turning translational research on its head is accelerating the pace of discovery in the immunotherapy field; hopefully, we can better tackle mechanisms of resistance and maximize the clinical benefit seen with these drugs.”