Chin, T. | Search bioRxiv

bioRxiv2025

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

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.

immunology↗

bioRxiv2024

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors

ABSTRACTMonocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

immunology↗