Early immunotherapy

Barcoding maps immune system components before cancer progresses

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NEW YORK—Lung cancer is the most common and most deadly cancer in the United States. Immunotherapy has achieved positive results in late-stage lung cancer patients. Now it is being applied to newly diagnosed patients, cutting the deadly disease off before it has the chance to take hold and offering a potential cure, according to a new Mount Sinai study published in Cell on May 4.
“Immunotherapy has mostly been used in advanced or metastatic lung cancer, but its benefit in early-stage tumors remains unknown. The standard treatment for early lung cancer is normally surgical removal of the lesions—sometimes with chemotherapy and radiation. Our study reveals that early lung lesions are heavily infiltrated with many different immune cells, suggesting that immunotherapy could also work on very early lesions and potentially lead to a cure by heading cancer off at the pass before it really takes root in the lungs,” said Dr. Miriam Merad, professor of oncological sciences and of medicine (hematology and medical oncology) at The Tisch Cancer Institute at Mount Sinai.
The article explains how the researchers “developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes.” The barcoding method allows a simultaneous single-cell analysis of the tumor, non-involved lung and blood cells to provide a “detailed immune cell atlas of early lung tumors.” 
The researchers showed that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and natural killer cell compartments, and identified changes in tumor-infiltrating myeloid cell (TIM) subsets that likely compromise antitumor T cell immunity. Paired single-cell analyses thus offer knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies.
The research, which identified many other immunotherapy targets to increase the number of patients that could benefit from immunotherapy, is being used to develop immunotherapy trials with early lung cancer patients. Dr. Raja M. Flores, chair of the Department of Thoracic Surgery at Mount Sinai Health System, and his team contributed significantly to the study by identifying patients and providing their tissue samples. Mount Sinai’s Human Immune Monitoring Center (HIMC) also played an integral role, by providing a platform to analyze patient samples using quality control assays and cutting-edge technology.  
The multidisciplinary team of thoracic surgeons, pathologists and scientists developed a comprehensive study. The patients’ lung tumor samples, samples of surrounding healthy lung tissue and blood samples were immediately analyzed on a cellular level to map out the immune system components present with a specially developed barcoding system.
This new research also identified a multitude of additional immunotherapy targets to increase the number of patients that would significantly benefit from immunotherapy, which at the moment remains fairly small. This research is being used to develop immunotherapy trials with early lung cancer patients.
The barcoding method attaches cells in each sample to a different metal isotope, enabling sample pooling for a simultaneous analysis of cells from all three tissue types. Combining this barcoding approach with high-dimensional profiling, the scientists mapped the complete immune landscape “to search for tumor-driven changes that would be vulnerable to targeted immunotherapy.”
By analyzing the samples, the researchers determined that stage I lung cancer lesions already harbor immune system components that are likely to compromise antitumor T cells’ ability to fend off cancer. These single-cell analyses offered detail of tumor-driven immune changes, providing a powerful tool for the future design of immunotherapies such as checkpoint inhibitors, particularly those that target the PD-1 and PD-L1 proteins that shield cancer from the immune system. These checkpoint inhibitors have shown great promise in later-stage cancers, according to Merad, who plans to build a portal to share the results of this study and of other HIMC research to collaborate with colleagues at other cancer centers in the hopes of promoting further cancer and immunology research. 

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