CDK4/6 inhibitors not only induce cell-cycle arrest but also promote antitumor immunity by stimulating the production of type III interferons, which enhance tumor antigen presentation, and suppress regulatory T cells. The immune effects of these drugs provide a rationale for combining CDK4/6 inhibitors with checkpoint blockade agents.
Cancer drugs designed to selectively disrupt cell-cycle progression have the added benefit of boosting antitumor immunity. According to a new study, CDK4/6 inhibitors accomplish this by increasing tumor antigen presentation and suppressing the proliferation of regulatory T cells (Treg)—immune-enhancing effects that together augment the cancer-killing potential of checkpoint blockers (Nature 2017;548:471–5).
CDK4/6 inhibitors such as palbociclib (Ibrance; Pfizer) and ribociclib (Kisqali; Novartis) have been shown to induce cell-cycle arrest but not apoptosis. Yet in patients with cancer, these drugs sometimes lead to tumor regression, even when taken as monotherapies. That has created a “clinical enigma,” says Christopher Klebanoff, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. “How can a drug that in a Petri dish causes the cancer cells to arrest, but not die, lead to cancer shrinkage in humans?”
To puzzle that out, a team from Harvard Medical School in Boston, MA, led by Jean Zhao, PhD, and Sandra S. McAllister, PhD, turned to a transgenic mouse model of mammary carcinoma. They reproduced the clinical observation that tumors can shrink following treatment with the CDK4/6 inhibitor abemaciclib (Eli Lilly). However, no such tumor regression was observed in nude mice that lack a thymus. “That suggested to us that maybe the adaptive immune response plays a role in CDK4/6 inhibitor efficacy,” says Harvard's Shom Goel, MD, PhD.
Goel and his fellow co–first author Molly DeCristo, PhD, went on to show that CDK4/6 inhibition promotes antitumor immunity in two ways: It stimulates the production of type III interferons by tumors, which increases their capacity to present antigens, and it reduces the number of immune-suppressive Tregs.
These effects collectively seemed to increase the potency of immunotherapy. In mouse models of breast and colorectal cancers, combined treatment with abemaciclib and an anti–PD-L1 antibody led to durable tumor shrinkage or complete tumor regression in the mice. Human trials that combine CDK4/6 inhibitors with anti–PD-L1 or anti–PD-1 antibodies are under way in patients with breast and lung cancers.
Mechanistically, the authors report that CDK4/6 blockade suppresses the activity of the DNA methyltransferase DNMT1. Reduced activity of this epigenetic regulatory enzyme increases the expression of endogenous retroviruses in the genome, producing double-stranded RNA that stimulates the interferon response within tumor cells. What's more, says Goel, DNMT1 inhibition may be responsible for suppressing Treg proliferation as well, although he acknowledges that other mechanisms might come into play.
Charles Sherr, MD, PhD, of St. Jude Children's Research Hospital in Memphis, TN, thinks there probably are. “I remain unconvinced that what is observed strictly depends upon DNMT1 or endogenous retrovirus expression,” he says. A possible alternative explanation is that cells rendered senescent by the drug therapy release cytokines and chemokines that recruit innate immune cells. He also notes that the reason why regulatory T cells appear more sensitive than cytotoxic T cells to CDK4/6 inhibitors remains unexplained.
“Regardless of the underlying mechanisms, the key point is that there is upregulation of neoantigens, and that sets up the situation for why anti–PD-1 might synergize with CDK4/6 inhibitors,” Sherr says. “That's the clinically relevant punch line.” –Elie Dolgin
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