Young and female patients with cancer may not respond as well to immunotherapy
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The immune cells of young and female individuals typically are very potent due to genetic and hormonal factors.
Research has shown that women have twice the antibody response to influenza vaccines and higher CD4-positive T-cell counts than men. This sexual dimorphism also is evident in the ability of young women’s immune systems to eradicate tumor cells relative to other patient populations.
Although generally considered an advantage, this immune efficiency may paradoxically lead to poorer responses to immunotherapy in these individuals, according to a study conducted by researchers at University of California San Diego School of Medicine and published in Nature Communications.
“The question we were committed to answering is why a lot of people don’t respond to immune checkpoint blockade,” study co-author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and head of the laboratory of immunology at UC San Diego Moores Cancer Center, told Healio. “We knew if we could figure that out, we might be able to either increase the rate of response, or simply select patients in a more accurate way so to avoid treating a patient who most likely will not respond.”
Zanetti and senior author Hannah Carter, PhD, associate professor of medicine at UC San Diego, explored the reasons for inconsistent response to immunotherapy by evaluating genomic information of nearly 10,000 patients with cancer.
Zanetti spoke with Healio about the value of understanding the immune mechanisms of different patient populations and how the current study may result in better selection of patients for immunotherapy.
Question: How did this study come about?
Answer: Dr. Carter and I developed this concept together; this work essentially originated over coffee. We were lucky enough to hit something right away, and we developed it into a full-fledged study.
We looked at a variety of parameters, including sex and age. It is obvious there is a sexual dimorphism in cell division that also affects immune response. Dr. Carter had recently developed an algorithm that enables one to assess the rate of erosion of the immune system’s ability to attack a cancer cell. It is a new, mathematics-driven way of looking at biological phenomena. It is also more precise, because the basis of the interaction between cancer cells and the immune system is chemistry. We found that individuals who are female and young accelerate erosion faster than men or older women. As an example, when cancer is discovered, depending on how you assess evolution of cancer in a specific individual, the chances of responding to immunotherapy are going to be proportionally decreased.
What it boils down to is that over time — and in a way that is different for men and women — tumor cells become more invisible to the immune system. The concept of visibility vs. invisibility reflects the chemical interaction that is necessary for recognition of cancer cells by immune cells.
Q: So, the stronger immune response of young and female patients leads to the lack of visibility of these cells?
A: This is the result of a more aggressive attack early in the tumor’s history. Women are known for mounting a more vigorous immune response upon vaccination. That haunts these patients when embarking on a long-term battle with cancer. They may start with an advantage, but as with many other things, the first response is used to select variants of cancer cells that can no longer be recognized. This is primarily because cancer is a chronic disease. It’s a long battle, and the battle is always in favor the tumor. If you can kill it immediately, the game is over, but if it becomes a chronic affair, whatever good the immune system initially did becomes a hindrance later, because it is running out of targets.
Q: Why do individuals who are young and female mount a more vigorous immune defense?
A: It’s part of their physiology. In general, women have greater responsibility in the evolution of the species. They give birth; men don’t. They have an apparatus which, during pregnancy, goes into silence and becomes tolerant to the fetus, but then they must protect it. The physiology has developed differently, and there is enough evidence that women respond better to vaccination than men do.
Q: Is there any way to improve these patients’ response to immune checkpoint inhibitors?
A: Immune checkpoint inhibitors probably are not the panacea for these patients. Even though immune checkpoint inhibitors have been placed within the broad category termed “personalized immunotherapy,” they are more like a big bang, if you will. If you are lucky, you will respond, if you have a hundred T cells to protect you. Those T cells have to go after targets, and if the number of targets has shrunk over time, there is very little T cells can do to protect you. It is a sort of wake-up call for T cells, but if the chemistry of the recognition is falling apart, there is no remedy.
As far as what can be done, first, we need to further develop a method to more precisely assess a single individual’s likelihood of responding. Second, we need to direct attention to other forms of immunotherapy so that the patient will not be at the mercy of what is essentially a blind detonation in the tumor microenvironment.
There is a lot of evidence from studies that women do not fare quite as well than men in checkpoint inhibitor trials. Not everyone agrees with that, but when we started to look for evidence, we found it. We are looking at the mechanism of chemical interaction between target and effector immune cells. That’s a little bit more precise than assessing clinical outcomes that may also depend on other factors.
I think this new information needs to be taken with a grain of salt, but we stand by our results that there is a difference, and it matches a good proportion of clinical evidence. We need to keep digging until we find a more accurate way of predicting who is likely to respond and who is not.
For more information:
Maurizio Zanetti, MD, can be reached at 500 Gilman Drive, La Jolla, CA 90293-0815; email: mzanetti@ucsd.edu.
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