While the success of immunotherapy for some cancer patients is well known, the relatively new treatment does not work for everyone. One group that are known to have lower response rates to some types of immunotherapy are young and/or female. A team from the University of California, San Diego (UCSD), School of Medicine now may have discovered to why that is.

Their findings suggest 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 work is published in Nature Communications in the article, “Strength of immune selection in tumors varies with sex and age.”

“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, PhD, associate professor of medicine at UCSD School of Medicine.

They found that the major histocompatibility complex (MHC) plays a role as a source of the variation in the strength of the immune selection in tumors. MHC molecules are displayed at the surface of most cells in the body. Cancerous cells use them to tell the immune system to clear them away before the problem gets out of control. Since tumor cells carry a lot of mutations that are presented, the immune system can readily detect and eliminate them.

But some tumor cells evade the immune system by presenting an inhibitory molecule that keeps the immune system from recognizing the MHC flags.

Immune checkpoint inhibitors come into play at this point, using antibodies to make the tumor cell once again visible to the patient’s immune system. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients.

So why would a person’s age or sex influence how well immune checkpoint inhibitors work? Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown.

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 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.

“So if a tumor cell doesn’t present highly visible, mutated self antigens to begin with, checkpoint inhibitor drugs can’t help reveal them to the immune system,” she said.

“This shows an important thing, that the interplay between the cancer genome and the adaptive arm of the immune system is not a static one,” said co-author Maurizio Zanetti, MD, professor of medicine at UCSD School of Medicine and head of the Laboratory of Immunology at UCSD Moores Cancer Center. “Two simple but important variables, age and sex, influence this interplay. The study also emphasizes the master role of the MHC in dictating the outcome of this interplay, reaffirming its central role in the evolution of disease, cancer included, at the level of the individual and population.”

Carter cautions that their findings for “younger” patients don’t necessarily apply to children since, genetically speaking, pediatric tumors are very different from adult tumors. In addition, she noted that, like most genomics databases, those used in this study contain data primarily from people of Caucasian descent, and more diversity is needed to confirm that the findings can be generalized to all populations.

“Cancer isn’t just one disease, and so the way we treat it can’t be one-size-fits-all,” she said. “All checkpoint inhibitors can do is remove the generic block that tumors put up to hide from the immune system. The more we learn about how interactions between tumors and immune systems might vary, the better positioned we are to tailor treatments to each person’s situation.”