A study by Ludwig Cancer Research reveals cell interactions essential to the ability of the immune system’s cytotoxic T lymphocytes to destroy ovarian tumors, and their involvement determines the effectiveness of checkpoint-blocking immunotherapy in a variety of cancers. Showed that it may help to.
Led by George Coukos, director of Ludwig Lausanne cancer cellDescribes the most killable invasive T lymphocytes (TILs) cancer The cells are in the islets inside Ovarian tumor..These islets will accommodate more Immune cells Known as antigen-presenting cells (APCs). Coukos and his team conducted TIL in cell culture and mouse experiments cancer cell It then supports those activities and stimulates a protein known as CD28 on TIL to enhance and maintain their function. It is this interaction that “licenses” TIL and destroys tumor cells when treated with anti-PD-1 checkpoint-inhibiting antibodies (which release the brakes imposed on TIL function).
“Ovarian cancer and many other types of cancer that have long resisted immunotherapy by knowing what TIL needs to maintain an immune attack against the tumor and what puts the tumor in that state. It opens the door for new therapeutic approaches to cancer, “says Coukos.
NS study In the first report, led by Coukos, in 2003, the most TIL-infiltrated ovarian cancer was associated with the longest survival of patients. Nevertheless, like most other cancers, cancers have proven to be relatively resistant to anti-PD-1 checkpoint-inhibiting immunotherapy.
Investigating this phenomenon, Coukos and his team created a profile of TIL from a sample of high-grade serous ovarian cancer (HGSOC), the most common and aggressive form of the disease. They found that the most effective antitumor TIL was in the islets within the tumor, not around the tumor. TIL in these tumors has been shown to be present in a variety of conditions, from activated and ready to attack, to varying degrees of fatigue, end-of-life fatigue, and permanent ineffectiveness. I am.
Microscopy and molecular analysis revealed that TIL, which is best able to attack tumors, is involved in bidirectional associations within the islets.
“Our findings explain why the presence of TIL, especially in tumor islets, has long been associated with a better prognosis for patients with ovarian cancer,” says Coukos. “Furthermore, they show that T cell CD28 co-stimulation by APC is not an exclusive problem with lymph nodes, but also occurs in the heart of tumors in tumor pancreatic islets that involve T cells. Tumor cells For destruction.We believe this interaction is the key to maintaining success Immune attack And it is the first to show in human tumors that successful T cells are supported by myeloid tissue rather than alone. “
Researchers also found that the most capable TIL also expresses the PD-1 molecule. This puts a brake on tumor-targeting activity. The brake is released by anti-PD-1 checkpoint inhibition. However, the ferocity and endurance of such post-treatment TIL attacks are highly dependent on their association with APC.
Studies have shown that APC activates TIL in these islets by binding to CD28. In fact, the ability of PD-1 blockade to activate TIL appears to depend on CD28-mediated co-stimulation.
These findings may be relevant beyond ovarian cancer. Researchers have identified signs of gene expression associated with effective TIL activation in ovarian tumors and found them to be more responsive to anti-PD-1 immunotherapy, such as melanoma and non-small cell lung cancer. It has been shown to be associated with cancer. Conversely, this sign is less common in tumors that do not respond to this treatment, such as colon cancer. In addition, distinct genetic signatures that reflect APC activation in tumors are associated with positive responses to checkpoint blockade in various tumor types.
Coukos and his colleagues have also discovered an anti-CTLA-4 immunotherapy that targets T’s separate brakes. cellEnhances anti-PD1 immunotherapy by allowing stimulation of CD28 on TIL. Taking this finding one step further, they found that the addition of an APC stimulator known as CD40L in combination with anti-PD-1 and anti-CTLA-4 blockade restored the antitumor activity of unresponsive TIL. Shown. Cell culture..
When this approach was tested in a study of mice transplanted with ovarian tumors, the researchers demonstrated that the combination of the three treatments was far superior. tumor Control in mouse models rather than either monotherapy or dual therapy.
The treatments considered in this study are already widely used or under clinical development, so the results of this study can be evaluated relatively quickly.
Ludwig Cancer Research
Quote: The study was an ovarian tumor obtained on November 6, 2021 from https: //medicalxpress.com/news/2021-11-cellular-interactions-essential-immune-ovarian.html (November 6, 2021) Identify cell interactions that are essential for immune attack on
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