Younger Adults, Women with Cancer Respond Less Well to Immunotherapy with Checkpoint Inhibitors

September 16, 2020

Younger and female patients with a variety of cancer types tend to have strong immune systems that naturally fight an array of cancer cells. The tumor cells the immune system doesn’t destroy are the most evasive, both to the immune system and medications that boost its activity, and this makes checkpoint inhibitor immunotherapy less effective in this population.

Because younger adults and women with cancer tend to have stronger immune systems than those who are older and/or male, their bodies are fairly efficient at killing cancer cells.

Unfortunately, that means that any malignant cells left alive by the immune system are typically very difficult for the body to detect and fight, which also makes them especially challenging to treat with immunotherapy. Those recent findings may explain why young and female patients tend to respond less well to immunotherapy drugs known as checkpoint inhibitors, which have been treatment game changers across many cancer types in recent years.

The conclusions came from a study conducted by researchers at the University of California San Diego School of Medicine and were recently 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, an associate professor of medicine at UC San Diego School of Medicine, in a press release.

Specifically, the study looked at major histocompatibility complexes (MHCs), biological mechanisms that broadcast information to the immune system about whether specific cells are acceptable or a threat. Researchers found that the immune systems of women and younger adult patients can detect many cancer-related MHC messages and kill the corresponding cells but tend to overlook cells that hide behind a weaker, less noticeable MHC presentation.

To conduct the study, Carter and her team looked at genomic information for nearly 10,000 patients with cancer, gleaned from The Cancer Genome Atlas of the National Institutes of Health; they also culled data about another 342 patients with cancer from the International Cancer Genome Consortium database and published studies.

The researchers measured results with their recently developed Patient Harmonic-mean Best Rank score, which rates the ability of MHC in individuals to present tumor cells to the immune system. They focused on a set of 1,018 genetic mutations known to drive the development and growth of cancer. Included in the study were 9,913 patients with MHC-I molecules and 7,174 patients with MHC-II molecules. The patients, who had cancer types that were not gender-specific, were divided into groups based on gender (male versus female) and age (younger versus older). They were evaluated for their ability to present each of the genetic mutations to the immune system via MHC-I and MHC-II.

The researchers did not find that MHC functioned differently based on sex or age. Rather, they observed that the robust immune systems of younger and female patients efficiently killed cells that carried obvious markers associating them with cancer, while leaving behind tumor cells that were less clearly marked.

“This study presents evidence that strength of immune selection during tumor development varies with sex and age and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy,” the authors wrote. “We posit that immune checkpoint blockade treatment is likely to have a reduced effect in younger female patients since this treatment will attempt to reactivate T cells for immunologically invisible neoantigens. Rather, adaptive T-cell therapy against patient-validated neoantigens or therapeutic vaccination against conserved antigens will likely be more beneficial in these patients.”