Cells exposed to carcinogens provide clues to fight treatment-resistant cancers

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New research from Massachusetts General Hospital explores how the independent effect of the mutation of environmental carcinogens leads to the recruitment of CD8 + T cells, the dominant antitumor cell type. Here, T cells (red and green) attack breast cancer cells exposed to carcinogens (light blue). Credit: Mei Huang, PhD

Researchers at Massachusetts General Hospital (MGH) have discovered a biological mechanism that transforms cells exposed to carcinogens from environmental factors such as smoking and ultraviolet light into immunogenic cells that can be used therapeutically to combat treatment-resistant cancers. As reported in Scientific advances, this mechanism involves stimulating the release of small proteins known as chemokines which, in turn, recruit antitumor immune cells (CD8+ T cells) at the tumor site to block metastasis, potentially enhancing the efficacy of a new generation of immunotherapies.

“Immunotherapists have shown tremendous promise in recent years, but the fact is that their response rate for many types of cancer is very low,” says lead author, Shadmehr (Shawn) Demehri, MD, Ph.D. D., researcher at the Center for Cancer. Immunology and Skin Biology Research Center at MGH. “We have shown how exposed to certain carcinogens become immunogenic, that is, they become targets of the immune attack and how this exposure can be harnessed to treat such important forms of such as breast cancer and other epithelial cancers “.

CD8+ T cells are known to effectively attack cells exposed to environmental carcinogens. But in the past, science has focused primarily on mutations caused by these exposures to a patient’s heritable DNA as a cause of immune attack. In their laboratory work with mice, the MGH team demonstrated for the first time another consequence of exposure that may have significant immunological implications, i.e., non-genetic alteration of cells through these harmful how to smoke, and pollution.

“This finding is particularly important because it could open the door to therapeutic interventions that are not practical with a DNA approach, as no clinician wants to introduce even more genetic mutations into cancer cells just to make them more immunogenic,” he explains. Demehri. “We found out if there was another immunogenic element associated with independent or even complementary carcinogen exposure to the presence of the mutation, then you could administer this factor to a ‘cold’ tumor to make it ‘hot,'” he said. which means it would become immunogenic and sensitive to immunotherapies. “

This factor is a chemokine known as CCL21, which MGH researchers found was expressed in breast cancer cells in mice that were exposed to DMBA, a carcinogen similar to that found in cigarette smoke. “By signaling, CCL21 recruits CD8+ T cells that infiltrate the tumor, as demonstrated in previous work, and are associated with a significant reduction in the relative risk of distant metastasis, ”says lead author Kaiwen Li, MD, researcher of the MGH Cancer Immunology Center, MGH Skin Biology Research Center and the Department of Urology of Sun Yat-sen Memorial Hospital of Sun Yat-sen University of China. “The CCL21 not only induces an antitumor immune response to prevent metastasis, but outperforms others known as Tregs (immunosuppressive regulatory T cells) present in tumors to inhibit the work of CD8+ T cells “.

As an example of how this unique mechanism could be used therapeutically, the MGH team reported that an injection of CCL21 into the tumor could transform cold breast cancers into hot tumors that respond to current immunotherapies.

“We hope the researchers will use these findings to open up a much broader field of research on cancer immunology,” Demehri stresses. “Specifically, studies are needed to identify the full range of cytokines and chemokines that are induced by environmental carcinogens in various types of cancer with the goal of harnessing the most potent mediators of antitumor immunity.”


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More information:
“CD8 + T Cell Immunity Blocks Breast Cancer Metastasis Exposed to Carcinogens” Scientific advances (2021). avances.sciencemag.org/lookup… .1126 / sciadv.abd8936

Citation: Cells Exposed to Carcinogens Provide Hints to Fight Treatment-Resistant Cancers (2021, June 18) Retrieved June 18, 2021 at https://medicalxpress.com/news/2021-06-carcinogen-exposed- cells-clues-treatment-resistant- cancers.html

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