Why Young And Female Cancer Patients Have Low Response Rate To Immunotherapy

Younger and female patients tend to accumulate more cancer-causing genetic mutations of the sort that MHCs can't present to the immune system as efficiently.

Gender and age differences have strong association with immune response. And this association is not confined to cancer only. Even in case of flu, female’s body generates twice as much antibody than male’s body. This association was found to be present in many autoimmune diseases as well.

But if females and younger people have stronger immune responses in most cases, you might expect cancer immunotherapy to work better for them, not worse.

But this does not happen in the case of cancer immunotherapy. To know the reason, researchers analyzed genomic information for nearly 10,000 patients with cancer available from the National Institutes of Health’s The Cancer Genome Atlas, and another 342 patients with other tumor types available from the International Cancer Genome Consortium database and published studies. They found no age or sex-related differences in MHC function.

Surface of the cancerous or infected cells have the flag polls, called molecules of the Major Histocompatibility Complexes (MHC). MHCs hold up antigen flags and display them to immune cell surveyors that are constantly checking for damaged or infected cells.

Younger and female patients tend to accumulate more cancer-causing genetic mutations of the sort that MHCs can’t present to the immune system as efficiently.

This is likely because robust immune systems of the young and female are better at getting rid of cells displaying well-presented mutant self-antigens, leaving behind tumor cells that rely more heavily on the poorly presented mutations. This selective pressure is known as immuno-editing.

“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,” she said.

“This shows an important thing, that the interplay between the cancer genome and the adaptive arm of the immune system is not a static one,” said 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. “Two simple but important variables, age and sex, influence this interplay. The study also emphasizes the master role of the MHC in dictating the outcome of this interplay, reaffirming its central role in the evolution of disease, cancer included, at the level of the individual and population.”

This is likely because robust immune systems of the young and female are better at getting rid of cells displaying well-presented mutant self-antigens, leaving behind tumor cells that rely more heavily on the poorly presented mutations. This selective pressure is known as immuno-editing.

“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,” she said.

“This shows an important thing, that the interplay between the cancer genome and the adaptive arm of the immune system is not a static one,” said 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. “Two simple but important variables, age and sex, influence this interplay. The study also emphasizes the master role of the MHC in dictating the outcome of this interplay, reaffirming its central role in the evolution of disease, cancer included, at the level of the individual and population.”

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