June 22, 2024

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Why are there frequent side effects of cancer immunotherapy?

Why are there frequent side effects of cancer immunotherapy?


Nature: Why are there frequent side effects of cancer immunotherapy? The latest study found a new role of PD-1.

Cancer immunotherapy, represented by immune checkpoint inhibitors , has changed the cancer treatment landscape. Among them, antibodies that block PD-1 or PD-L1 have been approved for the treatment of more than 25 different cancers.


PD-1 (programmed cell death receptor-1) , which is located on the surface of T cells, and PD-L1 (programmed cell death ligand-1) , which is located on the surface of tumor cells , PD-L1 binds to PD-1 , prompting tumor cells to gain immune escape. Therefore, blocking the binding between PD-1 and PD-L1 through inhibitors can help T cells regain the ability to kill tumors.

However, PD-1 blockade often causes T cells to attack healthy tissue other than cancer cells, causing serious, even life-threatening side effects that diminish the benefits of cancer immunotherapy.


On June 21, 2023, Nikhil Joshi’s team at Yale University published a research paper entitled: PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens in the journal Nature .

This latest study reveals that PD-1 acts as a gatekeeper of tissue homeostasis in healthy tissue, and that immunotherapy that blocks PD-1 disrupts this role, leading to immune-related adverse events. The findings could help scientists predict, treat and even prevent side effects of PD-1 blockade immunotherapy.


Why are there frequent side effects of cancer immunotherapy?



While we already know why blocking checkpoint receptors boosts anti-cancer immune responses, it’s not clear why these immunotherapies also cause adverse events in normal organs. The emergence of these adverse events suggests that checkpoint receptors like PD-1 continue to protect healthy tissue from immune attack in normal individuals.


Currently, doctors cannot predict which patients will experience these side effects and which healthy organs will be attacked by immunotherapy. These side effects may cause doctors to have to suspend immunotherapy for cancer patients, which negatively affects the anti-cancer effect of immunotherapy.


Nikhil Joshi , corresponding author of the paper and associate professor of immunobiology at Yale University, said that this study shows for the first time that PD-1 plays a key role in preventing T cells from attacking normal tissues in healthy individuals. Ways to treat side effects.


Our peripheral T cell pool contains self-reactive T cells , that is, T cells that attack our own cells, tissues and organs. Immune checkpoint receptors, such as PD-1, are thought to suppress autoreactive CD8 T cells, thereby inducing peripheral immune tolerance. However, this view is challenged by the high frequency of immune-related adverse events in cancer patients receiving checkpoint inhibitor therapy.


In this study, the research team developed a new generation of mouse models to address the role of PD-1 in preventing T cells from attacking healthy skin. In this model, skin-specific expression of T cell antigens in the epidermis elicits a local infiltration of antigen-specific CD8 T cells with effector gene expression profiles.


In this context, PD-1 acts by preventing tissue-infiltrating antigen-specific effector CD8 T cells from:

(1) acquiring a fully functional pathogenic differentiated state,

(2) secreting large numbers of effector molecules,

(3) entering epidermal antigen-expressing cells , thereby maintaining skin tolerance.


The research team then mimicked immunotherapy by blocking PD-1 and found that epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in mice with some of the same skin lesions seen in cancer patients treated with PD-1 blockade disease.

The research team also analyzed skin biopsies from cancer patients undergoing treatment and showed that they had clonal expansion of effector CD8 T cells in both diseased and non-lesional skin, confirming the data from the mouse experiments.


Why are there frequent side effects of cancer immunotherapy?


Cytotoxic CD8 T cells are also present in healthy skin and may be drivers of cutaneous immune-related adverse events during immunotherapy

These experimental data in mice and humans support a novel idea that immune checkpoint receptors like PD-1 act by allowing peripheral antigen-specific effector CD8 T cells to coexist with antigen-expressing cells in immune-pathological tissues, Thus playing the role of the gatekeeper of the homeostasis of the organization.

PD-1 blocking immunotherapy interferes with these physiological regulatory functions, leading to adverse events.


This research lays the foundation for future development and improvement of immunotherapies to avoid adverse events.








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Why are there frequent side effects of cancer immunotherapy?

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