Immunotherapy with checkpoint inhibitors is more effective in cancer patients who have elevated numbers of specific types of immune cells inside their tumors, a study suggests. Patients with a favorable combination of immune cells respond better to immunotherapies and benefit from improved overall survival.
Those findings also can help clinicians predict which patients will benefit most from therapy with checkpoint inhibitors, or modify the immune response of patients to increase their chances of successful treatment.
The study, “A natural killer-dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments,” was published in the journal Nature Medicine.
In a combination of experiments done in mouse models and human tumor samples, the study shows that when immune cells known as natural killer (NK) cells are activated in the tumors, they help boost the immune response against the tumor and improve the patient’s response to immunotherapy.
Cancers are frequently able to evade the immune system by expressing checkpoint proteins that work as “brakes” to keep immune responses in check.
Normally, these brakes prevent the immune system from attacking the body’s own tissues, but in cancer cells they keep the T-cells of the immune system from killing the tumor.
A new type of anti-cancer drug called checkpoint inhibitors work by blocking the checkpoint proteins made by immune system cells, such as T-cells, and some cancer cells. Examples of these medicines are the anti-PD1 therapies Keytruda (pembrolizumab) and Opdivo (nivolumab).
When checkpoint proteins are blocked, the T-cells’ response to tumors is reactivated and able to kill cancer cells more efficiently. Therapy with checkpoint inhibitors therapy has shown promising results, by successfully eliminating malignancies in about 20 to 40 percent of patients with melanoma and other types of cancer. However, there is still a large proportion of patients who do not respond to these therapies.
Researchers believe the answer to that lies in the diversity of immune cells present inside the tumor or its surroundings.
“If you want to stimulate T cells to attack cancer, do you need to recruit any specific allies in the tumor first?” Matthew Krummel, PhD, professor of pathology, member of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and senior author of the study, said in press release. “We didn’t know who were the good and bad partners within the immune system, so we began systematically taking apart tumors and asking of every cell type that was in it, ‘Can you activate T cells?’”
Indeed, Krummel’s lab found a kind of immune cells called stimulatory dendritic cells (SDCs) were required for more robust T-cell responses. Without SDCs, T-cells were unable to respond effectively to checkpoint inhibitors.
However, for SDCs to be recruited and survive within tumors, another kind of immune cells was needed. Those are the NK (natural killer) cells, and usually act as first responders to detect cancer cells.
“One of the fascinating discoveries here is that we’ve long known that natural killer cells — as their name implies — can also kill cancer cells directly,” Krummel said. “But here we are discovering that their power doesn’t lie just in their ability to eliminate threats, but also in their ability to communicate with other immune cells.”
Using tumor samples from melanoma patients and mouse models, the scientists identified NK cells as the core partners in the tumor community of immune cells, which control the levels of SDCs inside the tumor by releasing a specific messenger molecule (cytokine).
Inside the tumor, NK cells also seem to be in close contact with SDCs, helping them to survive. In melanoma patients, the numbers of both SDCs and NK cells significantly correlate with a patient’s responsiveness to anti-PD-1 immunotherapy, suggesting that the crosstalk between NK cells and SDCs in the tumor is crucial to the patient’s outcome.
“This was very exciting because there are currently examples of new immunotherapies targeting NK cells being tested in the clinic,” Kevin Barry, PhD, postdoctoral scholar at UCSF, and lead author of the study said. “If you could successfully find a way to increase NK cells in patients’ tumors, that could be a way to boost SDC levels and produce better responses to current immunotherapies.”
Another potential application of the findings is to find biomarkers — in the blood, for instance — of the presence of NK cells and SDCs to identify patients who are most likely to benefit from immunotherapy.
“Currently we depend on biopsies or surgically removed tumor samples, but if we could find correlates in the blood, it would make for [a] really useful clinical tool to identify patients who are likely to have a great response to immunotherapy,” Barry said.