Cancer immunotherapy refers to a range of procedures that strengthens the patient's own immune system against cancer cells. Unfortunately, other patients do not respond, as well.
A research team from the University of California, San Diego (UCSD) School of Medicine have inquired why patients who are either young or are females exhibit low response rates to some forms of cancer immunotherapy. The results of their study are published in the latest journal Nature Communications.
CAMBRIDGE, UNITED KINGDOM - DECEMBER 09: A scientist examining cells in a 96-well plate. These plates allow scientists to look at lots of cells at the same time and directly compare cells that have or have not been treated with a drug, at the Cancer Research UK Cambridge Institute on December 9, 2014, in Cambridge, England.
Strength of Immunity, Sex, and Age
In their report, the UCSD researchers found evidence that points to the commonly robust immune systems found in young and female patients. These are generally better at fighting against tumor cells. However, the cells that are left behind are not "as readily visible to the immune system," which makes them unresponsive to cancer immunotherapy.
"Now that we know why some patients don't respond as well to immunotherapy, we can begin developing more informed approaches to treatment decisions," said Hannah Carter, Ph.D., and an associate professor of medicine at UCSD School of Medicine. She cited the development of predictive algorithms for determining an individual's response before starting immunotherapies.
In the event of cancer cell development, the infected cells generate "molecular flags" that notifies the immune system, which in turn acts to clear them away in the early stages. This molecular flag is held up by the Major Histocompatibility Complexes (MHC), commonly appearing at the surface of cells in the body.
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These individual MHC genotypes are responsible for limiting the mutational landscape at the first stages of tumorigenesis—or the mutation into cancer cells. Furthermore, MHC's project antigen flags—information about the infected cells—so that the immune system may detect them.
Generated tumor cells carry various mutations that should make it easy for them to be detected, with the cells producing flags visible to the surveying system of the immune system.
However, some tumor cells manage to go around this detection process by raising the equivalent of a stop signal that prevents the immune system from identifying the cells with MHC flags. At this point, immune checkpoint inhibitors are employed. Cancer immunotherapy uses antibodies to force the tumor cell to raise flags and make them detectable again to the immune system.
The Difficulty of Young and Female Patients with Immune Checkpoint Inhibitors
The lack of responsiveness among young and female patients has been observed and inquired in previous studies. One of the most common observations is that female patients generally have twice the antibody response to vaccines, like flue, and they are more prone to acquiring autoimmune conditions.
Human immune systems, like other physiological organ systems, weaken with age. The paper also addresses the seemingly counterintuitive inverse relationship between age and gender with autoimmune responses. In this case, stronger immune response works against these people against cancer.
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The UCSD team analyzed genome information for some 10,000 patients, with the data taken from The Cancer Genome Atlas from the National Institute of Health. They also looked at other patients, 342 of them, with other tumor types with data from the International Cancer Genome Consortium database. They were not able to establish a link between age or gender with MHC function.
However, they were able to observe that younger patients and female ones tend to accumulate cancer-related mutations that MHC can't efficiently flag for the immune system. "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," Carter suggested.
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