Cancer Cell
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A trio of immune cells are key to immunotherapy response in hepatocellular carcinoma (HCC), according to new work from the Icahn School of Medicine at Mount Sinai. The research team found that interaction between mature dendritic cells, CXCL13+ T follicular-helper-like cells, and progenitor CD8 T cells helps to maintain a working CD8 T cell population, which supports immunotherapy success. Terminally “exhausted” CD8 T cells, meanwhile, were associated with non-response to immunotherapy.

“Terminally exhausted T cells will fail to expand upon PD-1 blockade, but the CD8 progenitor, in particular, can expand them (with the help of the triad we describe) upon PD-1 blockade,” Thomas Marron, MD, PhD, told Inside Precision Medicine. He is head of the Early Phase Trial Unit at the Mount Sinai Tisch Cancer Center, the clinical trial lead, and co-senior author of the study.

The team’s findings were published in Nature Medicine.

In general, cancers that have a good degree of immune infiltration—commonly termed “hot” tumors—respond well to immunotherapy.

“We compared these ‘hot’ responders and non-responders, and demonstrated that a specific organization—spatial interaction—of specific immune cells is found within tumors of patients who responded to immunotherapy compared to those who did not,” Marron said.

More than 800,000 people around the world are diagnosed with liver cancer each year, according to the American Cancer Society. HCC is the most common type of liver cancer.

Surgery is often used to treat this disease, but the cancer tends to spread within the liver as micrometastatic disease, which is hard to detect. As a result, doctors are using immunotherapy, both before and after surgery, to improve results.

“While checkpoint blockade has unquestionably revolutionized cancer treatment, most patients do not respond to immunotherapy. Understanding at the molecular level why only some patients respond will help identify novel targets for improving cancer treatment,” said senior study author Miriam Merad, MD, PhD, director of the Marc and Jennifer Lipschultz Precision Immunology Institute at Icahn Mount Sinai.

“This work follows a study our team recently published in The Lancet Gastroenterology & Hepatology reporting that immunotherapy administered before liver cancer surgery can kill tumors and likely residual cancer cells,” she added.

In this latest study, the research team analyzed tumor samples taken from 29 patients before and after treatment with checkpoint blockade. Using single-cell technology and computational platforms, the team identified distinct groups of immune cells within tumors that determined which patients responded positively to immunotherapy and which did not.

“Reactivation of a type of T cell called CD8 T cells by checkpoint blockade was known to be critical for clearing tumor cells. Our new study shows that killer CD8 T cells are only reactivated when in close proximity to two other immune cell types: dendritic cells, which educate CD8 T cells to recognize cancer cells, and helper CD4 T cells, which aid in activating the CD8 T cells,” said Alice Kamphorst, PhD, co-senior author of the study, and assistant professor of Oncological Sciences at the Precision Immunology Institute.

These recent studies were produced by  Mount Sinai’s TARGET platform—The Neoadjuvant Research Group to Evaluate Therapeutics, founded by Marron and Merad, which aims to “optimize the use of the new therapies being developed today.” In a 2022 Nature Medicine paper they wrote that “There are nearly 5,000 novel agents in preclinical or clinical development that aim to improve [cancer] outcomes.”

The team’s findings indicate these specialized immune cell niches control the reactivation of CD8 T cells and subsequent tumor eradication by checkpoint blockade. By deciphering the molecules pivotal to the formation of these niches within tumors, the researchers intend to identify novel therapeutic targets to use in combination with PD1 blockade and test these treatment combinations via the TARGET platform.

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