MSK Research Highlights, November 23, 2022

Laboratory coats hanging from pegs

New research from Memorial Sloan Kettering Cancer Center (MSK) and the Sloan Kettering Institute — MSK’s experimental research arm — finds tumor-associated macrophages that express a specific transcription factor might be targeted to improve immunotherapy; examines how different mutational processes impact individual cell genomes in cancer; sheds new light on cell senescence in cancer; and offers new models to aid the search for new treatments for mesothelioma.

IRF8-Expressing Tumor-Associated Macrophages Offer New Immunotherapy Target 

Tumor-associated macrophages — or TAMs — are key cells that help tumors evade the body’s immune defenders. TAMs that express the transcription factor IRF8 promote T cell exhaustion in cancer, according to a new study led by senior author Ming Li, PhD, a cancer immunologist at the Sloan Kettering Institute. Using a mouse model of breast cancer, the research team additionally showed that TAM-specific IRF8 deletion prevented the exhaustion of cytotoxic T lymphocytes and suppressed tumor growth. Furthermore, they found a TAM-IRF8 gene signature is aligned with T cell exhaustion in multiple types of cancer. The findings suggest targeting IRF8-dependent immune cells could offer a novel immunotherapy approach. Learn more in Immunity

Illuminating a new dimension of ‘evolvability’ in cancer 

A study from the labs of Sohrab Shah, PhD, who heads the computational oncology program at MSK, and Samuel Aparicio, PhD, of the University of British Columbia, examines how different mutational processes impact individual cell genomes in cancer. Looking at triple-negative breast cancer and high-grade serous ovarian cancer, the researchers identified three previously hidden states of variation that could influence cancer phenotype and evolution. “Overall, the study illuminates a new dimension on how endogenous mutational processes impact ’evolvability’ in cancer through profiling cell-to-cell genomic variation,” Shah explains. “How selection operates on this source of variation will be the subject of future studies on therapeutic response.” Learn more in Nature

Senescence dramatically alters how cells sense environmental cues 

Cell senescence — which arises though natural aging as well as the activation of oncogenes — is a double-edge sword. It can hinder the development of tumors and enhance the effectiveness of some therapies. It can also create a microenvironment that promotes relapse and metastasis. Drugs that target senescent cells are being investigated as treatments against cancer. Using a senescence-inducible mouse model of liver cancer, a new study by Sloan Kettering Institute’s Scott Lowe, PhD, Hsuan-An Chen, PhD, and Direna Alonso Curbelo, PhD (now at the Institute for Research in Biomedicine in Barcelona, Spain), and other colleagues, found senescent cells have a dramatically altered ability to send and receive environmental signals — including a rewired tissue-sensing program that can be induced therapeutically to enhance anti-tumor immunity. “We envision that investigating this and other tissue remodeling and sensing programs in pre- and post-treatment tumor biopsies (e.g. through transcriptomic or proteomic profiles) may expose new response biomarkers and/or combination strategies to improve the clinical management of cancer,” the researchers write. A parallel report from another group, also at the Institute for Research in Biomedicine in Barcelona, provides additional support in the ability of senescent cells to enhance anti-tumor immune responses. Learn more in Cancer Discovery.  

Models Will Help Find New Mesothelioma Treatments 

Diffuse pleural mesothelioma (DPM) is an aggressive disease with few therapeutic options for the approximately 3,300 individuals who are diagnosed annually in the U.S. Now, a team of researchers in the Charles M. Rudin Laboratory at Memorial Sloan Kettering Cancer Center have developed the largest cohort to date of DPM patient-derived xenograft (PDX) models, representing different disease stages and treatment histories. “Our data demonstrate that these mesothelioma PDX models closely resemble the genotype and phenotype of the original tumors, and identify pathways altered in DPM to inform ongoing drug discovery and improve patient outcomes,” says MSK medical oncologist Michael Offin, MD, who was co-first author of a study on the topic alongside MSK pathologist Jennifer L. Sauter, MD. Co-senior authors include Charles M. Rudin, MD, PhD, Marjorie G. Zauderer, MD, and Triparna Sen, PhD (now at the Tisch Cancer Institute). Learn more in Genome Medicine.