Why is cancer immunotherapy often ineffective for young women with cancer?

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Nature: Why is cancer immunotherapy often ineffective for young women with cancer?

Nature: Why is cancer immunotherapy often ineffective for young women with cancer?  The rise of cancer immunotherapy has opened up a new era of cancer treatment, and has brought new hope for the majority of cancer patients. However, it is regrettable that immunotherapy is not effective for everyone. For some cancer patients, especially young and female cancer patients, immunotherapy has little or no effect at all.

More importantly, although this particular phenomenon has made many doctors and researchers feel puzzled and confused, it has not been given a very reasonable explanation.

In August 2020, researchers from the University of California, San Diego School of Medicine published a research paper titled Strength of immune selection in tumors varies with sex and age in the journal Nature Communications, and found some explanations that “why young female patients are Evidence that the response to certain cancer immunotherapy is particularly low”.

This study pointed out that young patients and female patients have a typical and strong immune system that can better remove tumor cells from the body. Therefore, similar to natural selection, the remaining tumor cells are not easily detected by the immune system at the beginning, which also makes certain immunotherapies ineffective.

In this regard, Associate Professor Hannah Carter, the corresponding author of the article, said: “Now we know why some patients do not respond to immunotherapy. Therefore, we can develop more sensible immunotherapy methods for these special situations, or develop algorithms to predict the patient’s acceptance. The possible response rate of immunotherapy.”

The researchers found that the major histocompatibility complex (MHC) plays an important role in the change in the intensity of tumor immune selection. It is worth noting that MHC molecules are expressed on the surface of most cells in the human body and play a role in presenting antigens. Because tumor cells carry a large number of mutations, the immune system can easily find and eliminate them.

However, some tumor cells can evade immune system clearance by presenting an inhibitory molecule to prevent the immune system from recognizing MHC markers. In response to this situation, immune checkpoint inhibitors can play a reversal effect-through antibodies, tumor cells can be detected by the patient’s immune system again. In about 30% of cases, immune checkpoint suppression reactivates immunity to tumor cells that evade immune surveillance, but the response rate of this therapy is lower in young and female patients.

Comprehensive analysis of gender and age

So, why does age or gender affect the therapeutic effect of immune checkpoint inhibitors?

In fact, in terms of immune response, differences in gender and age have always been observed. For example, if a woman has two antibody responses to the flu vaccine, then she will be more likely to develop autoimmune diseases. Similarly, the human immune system will weaken with age. Young people have a stronger immune response in most cases, but this does not mean that cancer immunotherapy will be more effective for them.

In this study, the research team checked the genome information of nearly 10,000 cancer patients from the National Institutes of Health (NIH) Cancer Genome Atlas, as well as from the International Cancer Genome Alliance database and published research The genome information of 342 patients with other tumor types was obtained.

They found that there are no age- or gender-related differences in the function of MHC, but unexpectedly, compared with elderly and male cancer patients, younger and female patients tend to accumulate more oncogene mutations, which usually make MHCs Cannot be effectively presented to the immune system.

Gender and age-specific MHC driver mutations observed in the validation cohort

Hannah Carter explained: “This may be because the strong immune system of young and female is better able to clear tumor cells that present mutant antigens, while leaving behind those tumor cells that do not present antigens. This selective pressure is called immunoediting. Therefore, if tumor cells do not have highly visible, mutated self-antigens in the first place, immune checkpoint inhibitor drugs cannot help the immune system find them.”

Model of the relationship between immune selection and immunotherapy in tumor patients

This shows that the interaction between the cancer genome and the immune system is not a static process. Two simple but important variables, age and gender, affect this interaction. At the same time, the study also emphasizes the leading role of MHC in determining the outcome of this interaction, and redefines its core role at the individual and group levels in the evolution of many diseases, including cancer.

It is worth mentioning that the researchers emphasized that this study is not necessarily applicable to children, because from a genetic point of view, childhood tumors are very different from adult tumors. In addition, Hannah Carter also said that the data used in their study are mainly from people of Caucasian descent, so more research data is needed to confirm that this research conclusion can be generalized to all populations.

Cancer is not a simple disease, so the way to treat cancer cannot be one-size-fits-all. What immune checkpoint inhibitors can do is to remove the ordinary barrier that tumors hide from the immune system. The more we understand about the interaction between the tumor and the immune system, the better we can tailor a personalized treatment plan for each individual’s situation.

(source:internet, reference only)

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