TREM1 activation of myeloid cells promotes antitumor immunity

Abstract

Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.

Irreversible Electroporation-Induced Inflammation Facilitates Neutrophil-Mediated Drug Delivery to Enhance Pancreatic Cancer Therapy

“…Neutrophils are known to undergo apoptosis upon activation. C5a and TREM-1 are established neutrophil-activating agents that were substantially elevated after IRE (Figure E,F). , Consequently, the incubation of NP@NEs with IRE-treated tumor lysate induced neutrophil death and structure disintegration, along with the rapid release of DOX-BSA into the extracellular environment (Figure E,F). Such externalization of DOX-BSA from neutrophils was also observed in vivo under a fluorescence microscope, where the red fluorescent DOX-BSA diffused away from the green-fluorescent neutrophils and penetrated through the tumor mass (Figure F).…”

TREM1+ tumor-associated macrophages secrete CCL7 to promote hepatocellular carcinoma metastasis

“…The myeloid trigger receptor (TREM) family is an important family of receptors specifically expressed in myeloid cells and involved in many functions of myeloid cells. At the same time, they are also widely expressed on the surface of natural killer cells, B cells, T cells, epithelial cells and endothelial cells, indicating the importance of regulating innate immunity(Juric et al 2023 ). A study has shown that TREM1 is highly expressed in hepatocellular carcinoma tissue and significantly promotes the proliferation and invasion of HCC cells(Duan et al 2015 ).…”

Critical role of CD206+ macrophages in promoting a cDC1-NK-CD8 T cell anti-tumor immune axis

“…Overall, our results indicate that even this subset-dependent depletion of Mono/Mac populations may not be prudent in all contexts. To this extent, while anti-CSF1R antibodies have failed to show benefits in clinical trials ( 35 ), other strategies using for example, drugs that modulate specific subsets such as those expressing TREM2 or trigger others by engaging TREM1 may prove more surgical( 36 ). Systematically dissecting the role of individual TAM subtypes will continue to be crucial to deciphering their context-dependent and complex roles in the TME, with a view towards harnessing them for better immunotherapy outcomes.…”