TREM2 macrophages are associated with enhanced response to PD-1 blockade in human hepatocellular carcinoma

Pauline Hamon; Matthew D. Park; Jessica Le Bérichel; Merav Cohen; Brian Y. Soong; Mark Buckup; Clotilde Hennequin; Katherine E. Lindblad; Raphaël Mattiuz; Igor Figueiredo; Alexandra Tabachnikova; Travis Dawson; Darwin D’souza; Leanna Troncoso; Giorgio Ioannou; Colles O. Price; Nicolas Fernandez; Amir Giladi; Oren Barboy; Zhen Zhao; Sinem Ozbey; Sarah Cappuyns; Amanda Reid; Steven Hamel; Joel Kim; Romain Donné; Christie Chang; Robert Marvin; Hiyab Stefanos; Grace Chung

doi:10.1101/2025.09.09.675071

ImmunologybioRxivSep 9, 2025

Preprint

TREM2 macrophages are associated with enhanced response to PD-1 blockade in human hepatocellular carcinoma

Pauline Hamon iD, Matthew D. Park iD, Jessica Le Bérichel iD, Merav Cohen iD, Brian Y. Soong iD, Mark Buckup iD, Clotilde Hennequin, Katherine E. Lindblad iD, Raphaël Mattiuz iD, Igor Figueiredo iD, Alexandra Tabachnikova iD, Travis Dawson iD, Darwin D’souza iD, Leanna Troncoso iD, Giorgio Ioannou iD, Colles O. Price, Nicolas Fernandez, Amir Giladi iD, Oren Barboy iD, Zhen Zhao iD, Sinem Ozbey iD, Sarah Cappuyns iD, Amanda Reid iD, Steven Hamel iD, Joel Kim, , Miriam Mérad iD

Abstract

Macrophages are known to dampen tumor immunity. However, identifying druggable targets that modulate these cells to improve existing immunotherapies has been limited by a dearth of studies identifying macrophages that associate with pathological response to immune checkpoint blockade. To fulfill this unmet clinical need, we leveraged transcriptional and spatial profiling of specimens collected from a Phase II clinical trial studying neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC). We determined that the intratumoral abundance of TREM2-expressing macrophages and serological levels of soluble TREM2 are elevated in patients who responded to PD-1 blockade, compared to non-responders. We validated these findings in a second HCC cohort and in the IMbrave150 trial. These highlight the robust potential for TREM2 macrophages to predict therapeutic responses of HCC to immunotherapy. Therefore, our study provides a novel basis for the use of TREM2 macrophages to strategize treatment for patients with HCC to maximize therapeutic benefit.

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