Cancer immunotherapy — empowering a patient’s own immune system to clear away tumors on its own — holds great promise for some patients. But for other patients, immunotherapy just doesn’t work.
Researchers at University of California San Diego School of Medicine have found evidence that helps explain why patients who are young and/or female have especially low response rates to some types of cancer immunotherapy, sciencedaily.com reported.
Their findings suggested that since the typically robust immune systems of young and female patients are better at getting rid of tumor cells, the cells left behind are not as readily visible to the immune system to begin with, rendering some types of immunotherapy ineffective.
The study was published in Nature Communications.
“Now that we know why some patients don’t respond as well to immunotherapy, we can begin developing more informed approaches to treatment decisions — for instance, developing predictive algorithms to determine a person’s likely response before initiating immunotherapies that may have a high probability of not working or working poorly for them,” said senior author Hannah Carter, Ph.D., associate professor of medicine at UC San Diego School of Medicine.
Cancerous or infected cells wave molecular flags that tell the immune system to clear them away before the problem gets out of control. The flag poles — molecules of the Major Histocompatibility Complexes (MHC) — are displayed at the surface of most cells in the body. MHCs hold up antigen flags — bits of just about everything from inside the cells — and display them to immune cell surveyors that are constantly checking for damaged or infected cells. Since tumor cells carry a lot of mutations, they show up frequently among these flags, allowing the immune system to detect and eliminate them.
But some tumor cells evade the immune system by also throwing up a stop sign molecule that keeps the immune system from recognizing the MHC flags. And here’s where immune checkpoint inhibitors come in: This type of cancer immunotherapy uses antibodies to make the tumor cell once again visible to the patient’s immune system.
So why would a person’s age or sex influence how well immune checkpoint inhibitors work?
Sex and age differences have long been observed when it comes to immune response. For example, females have twice the antibody response to flu vaccines and are far more susceptible to autoimmune diseases. Similarly, human immune systems tend to weaken as we age. But if females and younger people have stronger immune responses in most cases, you might expect cancer immunotherapy to work better for them, not worse.
To get to the bottom of this conundrum, Carter’s team looked at genomic information for nearly 10,000 patients with cancer available from the National Institutes of Health’s The Cancer Genome Atlas, and another 342 patients with other tumor types available from the International Cancer Genome Consortium database and published studies. They found no age or sex-related differences in MHC function.
What they did find was that, compared to older and male patients with cancer, younger and female patients tend to accumulate more cancer-causing genetic mutations of the sort that MHCs can’t present to the immune system as efficiently. Carter said this is likely because robust immune systems of the young and female are better at getting rid of cells displaying well-presented mutant self-antigens, leaving behind tumor cells that rely more heavily on the poorly presented mutations. This selective pressure is known as immuno-editing.
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