A study by Ludwig Cancer Research has found how to revive a potent but functionally inert subset of anticancer immune cells that are often found within tumors for cancer therapy.
Led by Ping-Chih Ho of Ludwig Lausanne and Li Tang of the École Polytechnique Fédérale de Lausanne, the study describes as an immune factor known as interleukin-10 orchestrating the functional reactivation of T lymphocytes (TIL) that infiltrate tumors (terminally depleted), which have so far been shown to be impervious to stimulation by immunotherapy. It also shows that the factor, when applied in combination with cell therapies, can remove tumors in mouse models of melanoma and colon cancer. The conclusions are presented in the current issue of Immunology of nature.
“We have verified, for the first time, that terminally depleted TILs can be directly rejuvenated so that their potent anticancer activity is restored and that this rejuvenation is achieved through metabolic reprogramming of the TIL. cells induced by interleukin-10, ”said Ho, an associate member of the Ludwig Institute for Cancer Research in Lausanne.
Deprived of oxygen and vital nutrients within tumors, TILs are the most capable of killing cancer cells they tend to push into a stubbornly slow state known as exhaustion. Recent research has identified two different types of depleted TIL. One of them, known as “progenitor-depleted” TIL, can recognize cancer cells with nominal efficiency and proliferate in response to blocking PD-1 immunotherapy. But it is their offspring, the “terminally depleted” TILs, who are best equipped to detect and destroy cancer cells. However, they have functional disabilities, are prone to self-destruction, and are unable to proliferate.
“Even the PD-1 blockade cannot restore the function of these terminally depleted TILs,” Ho said. “In fact, many patients do not respond to PD-1 blockade because their tumors do not have depleted progenitor TILs and only have terminally depleted TILs. That is why researchers are looking for ways to revive terminally depleted T cells by in cancer therapy “.
Three lines of evidence propelled the current study. First, Ho and his team recently he showed that terminally depleted TILs could be functionally recovered by restoring the health of their mitochondria: the bean-shaped organelles of cells that generate energy and help regulate metabolism. Second, IL-10 is known to stimulate cancer immune responses and has been tested as a therapy for lung cancer in an early-stage clinical trial, albeit with mixed results. Finally, IL-10 was recently found to restore the mitochondrial form and reprogram the metabolism of immune cells known as macrophages.
Ho and colleagues questioned whether IL-10 could similarly influence terminally depleted TILs.
To find out, they added a designed, long-lived version of IL-10 (IL-10 / Fc) to adoptive cell therapy (ACT) —the infusion of tumor-targeted T cells to treat cancer — and tested the combination on a melanoma mouse model. Treatment increased the number and functionality of terminally depleted TILs and resulted in regression and tumor cures in 90% of treated mice, compared with limited regressions with IL-10 / Fc alone and none with ACT only. It should be noted that 80% of the surviving mice developed an immune memory for cancer, spontaneously rejecting the same tumors implanted two months after therapy.
“This suggests that if IL-10 is added to ACT, it could confer long-term protection against cancer growth,” Ho said.
The researchers also tested IL-10 / Fc in CAR-T cells, designed to target cancer cells with specific molecular markers. CAR-T cells treated with IL-10 / Fc induced complete cures of approximately 90% of implanted mice colon cancer tumors.
Ho, Tang and colleagues found that IL-10 / Fc acts specifically on terminally depleted TILs, not on parent-depleted TILs. They also showed that it reprograms the metabolism of terminally depleted TILs, starting with the process they use to extract energy from nutrients. This, in turn, leads to radical changes in their gene expression programs, which drives their functional reactivation and proliferation. IL-10 / Fc had the same effect on human TILs and also on CAR-T cells.
Researchers are now investigating the precise mechanisms by which metabolic reprogramming alters gene expression patterns in terminally depleted TILs. They are also conducting preclinical studies to advance the application of their findings to humans. cancer therapy.
Yugang Guo et al, Metabolic reprogramming of IL-10-terminated CD8 + T cells enhances antitumor immunity, Immunology of nature (2021). DOI: 10.1038 / s41590-021-00940-2
Ludwig Institute for Cancer Research
Citation: A research study finds ways to revive potent immune cells for cancer therapy (2021, May 24) recovered on May 24, 2021 at https://medicalxpress.com/news/2021-05- revive-potent-immune-cells-cancer.html
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