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Why don’t young and female patients respond to cancer immunotherapy?

Cancer immunotherapy – plays a promising role in the treatment of cancer in some individuals. It empowers a patient’s immune system to clear away tumours on its own. But for some other patients, immunotherapy doesn’t work.

The researchers from the University of California San Diego School of Medicine have found evidence of why some patients show low response to cancer immunotherapy. The patients who don’t respond to immunotherapy are young and female patients. Nature Communications published this study on August 17, 2020.

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Who doesn’t respond to cancer immunotherapy?

Their research suggests that since the young and female patients’ immune systems are better at getting rid of tumour cells. But the cells left behind are not visible to the immune system, to start. This process leads to rendering some types of ineffective immunotherapy.

Hannah Carter, Ph.D., is a senior author and associate professor of medicine at UC San Diego School of Medicine. Hannah said, “Now we know why some patients don’t respond as well to immunotherapy, we can begin developing more informed approaches for making treatment decisions.” She also added that “Developing predictive algorithms to determine a person’s response before initiating immunotherapies is important.” Furthermore, this prediction would help to identify whether the patients would respond to immunotherapy or not.

cancer immunotherapy

Role of MHC in cancer cells

Cancerous or infected cells have molecular flags – helps the immune system to clear them away before the infection becomes severe. Furthermore, the flag poles are the molecules of the Major Histocompatibility Complexes (MHC). They are present at the surface of most cells in the body. Moreover, they hold up antigen flags, which are bits of just about everything from inside the cells. These MHCs display the bits to the immune cell surveyors that are continually looking for infected or damaged cells. Since there are a lot of mutations in cancer cells, they mostly show up among these flags. Furthermore, this could help the immune system to detect and eliminate them.

But some tumour cells evade the immune system by throwing up a stop sign molecule that keeps the immune system from recognising the MHC flags. And here comes the immune checkpoint inhibitors: This type of cancer immunotherapy uses antibodies to make patient’s tumour cells visible to the immune system.

Why would a person’s age or sex influence checkpoint inhibitors?

When it comes to immune response, sex and age differences have long been observed. For instance, females are more susceptible to autoimmune diseases. At the same time, they have twice the antibody response to flu vaccines. Similarly, the human immune system tends to weaken as the age increases. As females and younger people have more robust immune responses in most cases, you might think cancer immunotherapy would work better for them, not worse.

To get to the reason behind this problem, Hannah’s team looked at genomic information for nearly 10,000 patients with cancer available from the National Institutes of health’s The Genome Atlas. Along with that, another 342 patients with other cancer available from the International Cancer Genome Consortium database and published studies. Surprisingly, they found no age or sex-related differences in MHC function.

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The reason behind the low response to cancer immunotherapy

What they found was that younger and female patients tend to accumulate more cancer-causing mutations than older and male patients with cancer, which MHCs can’t present to the immune system efficiently. Hannah said that the young and female people’s immune system is better at getting rid of only visible mutant cells. And so it leaves behind tumour cells that rely more on the poorly presented mutations. This selective pressure is called immune-editing.

Hannah said that if the cancer cells don’t show mutated self-antigens, the checkpoint inhibitors drugs can’t present them to the immune system.

Maurizio Zanetti, MD, is a co-author and professor of medicine at UC San Diego School of Medicine and head of the Laboratory of Immunology at UC San Diego Moores Cancer Center. “This shows an important thing that the cancer genome and the adaptive arm of the immune system is not a static one,” said Zanetti. He also added that age and sex are the two factors that influence this system.

Summary of the research

Hannah mentioned, “Our findings for ‘younger’ patients don’t apply to children since, pediatric tumours are different from adult tumours.” She also noted that “Most of the databases used in this study are from people of Caucasian descent and need more diversity to confirm the findings to be generalised to all populations.”

“Cancer is not a single disease and the way we treat it can’t fit all,” said Hannah. The more we learn about the tumour and immune systems’ interactions, the better we are to achieve every person’s situation.

Get more information from the article, “Strength of immune selection in tumours varies with sex and age.”

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