Cancer immunotherapy could be safer

Immunotherapy side effects caused by proteins that protect healthy tissue.

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In healthy people, self-reactive T cells are present in the peripheral T cell repertoire. Checkpoint receptors, like PD-1, are hypothesized to make it possible to delete or energize self-reactive CD8 T cells to induce peripheral tolerance.

Cancer immunotherapy has transformed the treatment of several types of cancer by stimulating the immune system‘s reaction to tumors. Immunotherapies that block checkpoint receptors like PD-1, proteins that limit T cell assault capacity, have emerged as the treatment of choice for various solid cancers.

However, using PD-1-blocking drugs can frequently result in T cells attacking healthy tissues and cancer cells, resulting in severe adverse effects that can negate the benefits of immunotherapy.

A new study published in Nature sheds fresh light on how PD-1 works to preserve healthy tissues, which can help scientists predict, treat, and avoid the negative effects of PD-1-blocking immunotherapies.

Scientists from yale university suggest that inhibiting checkpoint receptors improves anti-cancer immune responses. However, they don’t understand why these immunotherapies negatively affect normal organs. These undesirable outcomes show that checkpoint receptors such as PD-1 continuously protect healthy tissues from immune attacks in normal people.

Doctors are now unable to identify which patients are likely to experience such adverse effects or which healthy organs would be assaulted due to immunotherapy.

Side effects may cause doctors to discontinue immunotherapy or prescribe immunosuppressants, which harm immunotherapy’s anti-cancer benefits.

Nikhil Joshi, associate professor of immunobiology and senior author of the study, said, “Our findings show for the first time that PD-1 has a critical role in preventing T cells from attacking normal tissues in healthy individuals and may one day help find ways to reduce or prevent the side effects of immunotherapy.” 

Martina Damo led a team that created new generation mouse models to investigate the role of PD-1 in stopping T lymphocytes from invading healthy skin. They discovered that mice had several of the same skin abnormalities as cancer patients treated with PD-1 blockers.

The findings in mice and humans support that checkpoint receptors like PD-1 act as gatekeepers of tissue homeostasis by enabling functional T lymphocytes to exist in peripheral organs without causing immunopathology.

Researcher said. “We propose that PD-1-blocking immunotherapies interfere with these physiological regulatory functions, thus resulting in adverse events. This study lays the ground for developing improved immunotherapies that avoid adverse events.”

Journal Reference:

  1. Martina Damo, Hornick, et al. PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens. Nature. DOI: 10.1038/s41586-023-06217-y

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