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Trio of Immune Cells Within Tumor Niches May Be Linked to Immunotherapy Response in Liver Cancer

By: Amy MacDonald, MS
Posted: Friday, July 14, 2023

Immunotherapy that disrupts the PD-1/PD-L1 pathway is an evolving component of perioperative surgical care in hepatocellular carcinoma. Although PD-1 blockade may result in pathologic responses in some patients with this type of liver cancer, other patients do not respond. It is known that response to immune checkpoint blockade has been associated with an increase in tumor-infiltrating, PD-1–high, CD8-positive T cells, yet it is unclear why some of these T cells become exhausted and lose their cytotoxic properties, whereas others maintain potency.

Thomas U. Marron, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues hoped to uncover the specific attributes of the tumor microenvironment in hepatocellular carcinoma that facilitated response to PD-1 blockade. Published in Nature Medicine, their research revealed that intratumoral expansion of specific CD4-positive T-helper cells (CXCL13-positive, CH25H-positive, IL-21–positive, PD-1–positive), and effector-like CD8-positive T cells (granzyme K–positive) seemed to be correlated with an effective cytotoxic T-cell response, whereas the presence of “terminally exhausted” CD8-positive T cells (CD39-high, TOX-high, PD-1–high) was predictive of a poor response. Moreover, this cytotoxic T-cell reinvigoration occurred preferentially in tumor niches rich with mature dendritic cells.

“Our new study shows that killer CD8-positive T cells are only reactivated when in close proximity to two other immune cell types: dendritic cells, which educate CD8-positive T cells to recognize cancer cells, and helper CD4-positive T cells, which aid in activating the CD8-positive T cells,” stated study coauthor Alice O. Kamphorst, PhD, also of the Icahn School of Medicine, in a Mount Sinai press release.

The researchers analyzed 29 hepatocellular carcinoma lesions (and matched nontumor liver specimens) from patients who had received neoadjuvant cemiplimab-rwlc or nivolumab and were characterized as responsive or resistant to therapy. Paired single-cell RNA sequencing or single-cell T-cell receptor sequencing, cellular staining or imaging techniques were then used to characterize the molecular profiles of 918,811 immune cells across tumor and adjacent tissues, ultimately revealing clues to T-cell reactivation following PD-1 blockade.

Nature Medicine

Disclosure: For full disclosures of the study authors, visit

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