{"id":49348,"date":"2024-05-15T10:31:02","date_gmt":"2024-05-15T17:31:02","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=49348"},"modified":"2024-05-15T14:54:11","modified_gmt":"2024-05-15T21:54:11","slug":"this-time-its-personal-enhancing-patient-response-to-cancer-immunotherapy","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/es\/news-release\/this-time-its-personal-enhancing-patient-response-to-cancer-immunotherapy\/","title":{"rendered":"This time, it\u2019s personal: Enhancing patient response to cancer immunotherapy"},"content":{"rendered":"

LA JOLLA\u2014Immunotherapy has revolutionized the way we treat cancer in recent years. Instead of targeting the tumor itself, immunotherapies work by directing patients\u2019 immune systems to attack their tumors more effectively. This has been especially impactful in improving outcomes for certain difficult-to-treat cancers. Still, fewer than half of all cancer patients respond to current immunotherapies, creating an urgent need to identify biomarkers that can predict which patients are most likely to benefit.<\/p>\n

\"Front<\/a>
Front Row: Shitian Li, Helen McRae, Matthew Maxwell, Diana Hargreaves; Jingting Yu, and Susan Kaech.
Back Row: Braden Stevenson, Joshua Bell, Alexander Jones, Samuel Rivera, and Gerald Shadel.<\/p>\n

Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n

Recently, scientists have noticed that patients whose tumors have a mutation in a gene called ARID1A<\/em> are more likely to respond positively to immune checkpoint blockade, a type of immunotherapy that works by keeping cancer-fighting immune cells called T cells turned \u201con\u201d when they\u2019d otherwise be turned \u201coff.\u201d Since this ARID1A<\/em> gene mutation is present in many cancers\u2014including endometrial, ovarian, colon, gastric, liver, and pancreatic cancers\u2014researchers at the Salk Institute wondered how it contributes to treatment sensitivity, and how clinicians can use this information to customize cancer treatments to each patient.<\/p>\n

The new study, published in C\u00e9lula<\/a><\/em> on May 15, 2024, reveals that ARID1A<\/em> mutation renders tumors sensitive to immunotherapy by inviting cancer-fighting immune cells into the tumor through an antiviral-like immune response. The researchers suggest this mutation and antiviral immune response could be used as a biomarker to better select patients for specific immunotherapies, like immune checkpoint blockade. The findings also encourage the development of drugs that target ARID1A and related proteins as a way of sensitizing other tumors to immunotherapy.<\/p>\n

\u201cThis could really make a difference in patient outcomes from cancer treatment,\u201d says Associate Professor Diana Hargreaves<\/a>, senior author of the study. \u201cThese ARID1A<\/em> mutation cancer patients are already having an immune response, so all we need to do is upregulate that response using immune checkpoint blockade to help them destroy their tumors from the inside.\u201d<\/p>\n

While it was reported that people with ARID1A<\/em> mutations responded well to immune checkpoint blockade, the exact relationship between the two remained unclear. To elucidate the mechanism behind this, Salk scientists turned to mouse models of melanoma and colon cancer with either mutated ARID1A or functional ARID1A.<\/p>\n

\"An<\/a>
An ARID1A gene-deficient human endometrial tumor being infiltrated by CD8+ T cells (yellow). All cell nuclei are colored blue, including tumor cells and CD8+ T cells.<\/p>\n

Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n

The team observed a powerful immune response in all animal models with mutated ARID1A<\/em> tumors but not those with functional ARID1A<\/em> tumors, supporting the idea that the ARID1A<\/em> mutation was, indeed, driving the response. But how did this work on a molecular level?<\/p>\n

\u201cWe found that ARID1A<\/em> plays an important role in the nucleus of keeping DNA properly arranged,\u201d says Matthew Maxwell, first author of the study and a graduate student in Hargreaves\u2019 lab. \u201cWithout functional ARID1A<\/em>, loose DNA can be excised and escape into the cytosol, which activates a coincidentally desirable antiviral immune response that can be further enhanced by immune checkpoint blockade.\u201d<\/p>\n

El ARID1A<\/em> gene codes for a protein that helps regulate the shape of our DNA and maintain genome stability. When ARID1A is mutated, a microscopic chain of events analogous to a Rube Goldberg machine is set off in the cancer cell. First, the lack of functional ARID1A leads to escape of DNA into the cytosol. Next, the cytosolic DNA activates an antiviral alarm system\u2014the cGAS-STING pathway\u2014since our cells are adapted to flag any DNA in the cytosol as foreign to protect us against viral infections. Finally, the cGAS-STING pathway calls on the immune system to recruit T cells into the tumor and activates them into specialized cancer-killing T cells.<\/p>\n

\"A<\/a>
A Rube Goldberg machine illustrates the studied immunotherapy pathway. The scissors represent the ARID1A mutation and its effect on chromatin structure. Birds with DNA tails flying away represent DNA leaving the nucleus into the cytosol. The falling balls represent the cGAS-STING and Type I Interferon pathways, which sound the alarm to trigger an immune response. Finally, arrows representing T cells are released at a target with a crab in its center, representing cancer.<\/p>\n

Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n

With each step relying on the last, this chain of events\u2014ARID1A<\/em> mutation, DNA escape, cGAS-STING alarm, T cell recruitment\u2014results in more cancer-fighting T cells in the tumor. Immune checkpoint blockade can then be used to ensure these T cells stay \u201con,\u201d supercharging them to defeat the cancer.<\/p>\n

\u201cOur findings provide a novel molecular mechanism by which ARID1A<\/em> mutation can promote an anti-tumor immune response,\u201d says Hargreaves. \u201cWhat\u2019s most exciting about these results is their translational potential. Not only can we use ARID1A<\/em> mutations to help select patients for immune checkpoint blockade, but we now also see a mechanism by which drugs that inhibit ARID1A<\/em> or its protein complex could be used to further enhance immunotherapy in other patients.\u201d<\/p>\n

By outlining the mechanism by which immune checkpoint blockade is more effective for ARID1A<\/em> mutant cancers, the researchers have provided cause for clinicians to prioritize the immunotherapy for patients with mutated ARID1A<\/em>. The findings are a major step in personalizing cancer treatment and inspiring novel therapies that target and inhibit ARID1A<\/em> and its protein complex.<\/p>\n

In the future, the Salk team hopes its findings can improve patient outcomes across the many cancer types associated with ARID1A mutations and is set to explore this clinical translation with collaborators at UC San Diego.<\/p>\n

Other authors include Jawoon Yi, Shitian Li, Samuel Rivera, Jingting Yu, Mannix Burns, Helen McRae, Braden Stevenson, Josephine Ho, Kameneff Bojorquez Gastelum, Joshua Bell, Alexander Jones, Gerald Shadel, and Susan Kaech of Salk; Marianne Hom-Tedla and Katherine Coakley of Salk and UC San Diego; Ramez Eskander of UC San Diego; and Emily Dykhuizen of Purdue University.<\/p>\n

The work was supported by the National Institutes of Health (NCI CCSG P30 014195, T32DK007541, R01 CA228211, R01 CA285867, R01 CA216101, R01 CA240909, R01 AI066232, R21 MH128678, S10-OD023689), National Science Foundation, Howard Hughes Medical Institute, Cancer Research Institute, Pew-Stewart Scholars for Cancer Research, American Cancer Society, and Padres Pedal the Cause.<\/p>","protected":false},"featured_media":49385,"template":"","faculty":[74],"disease-research":[46,447,122,172],"class_list":["post-49348","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-diana-hargreaves","disease-research-cancer-biology","disease-research-colorectal-cancer","disease-research-immune-system-biology","disease-research-pancreatic-cancer"],"acf":[],"yoast_head":"\nThis time, it\u2019s personal: Enhancing patient response to cancer immunotherapy - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/es\/news-release\/this-time-its-personal-enhancing-patient-response-to-cancer-immunotherapy\/\" \/>\n<meta property=\"og:locale\" content=\"es_MX\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"This time, it\u2019s personal: Enhancing patient response to cancer immunotherapy - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Immunotherapy has revolutionized the way we treat cancer in recent years. 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