Abstract C105: Targeting of TREM1+ myeloid cells to promote antitumor immunity
Authors: Juric Vladi , Chan Chris , Mayes Erin , Norng Manith , Le Tiep , Dash Subhadra , Sriram Venkataraman , Lu Erick , Pollack Joshua L. , Binnewies Mikhail , Waszczuk Joanna , Du Xiaoyan , Mankikar Shilpa , Pal Aritra , Baker Kevin P. , Liang Linda 
Published: March 2020

Abstract
The tumor microenvironment contains diverse types of myeloid cells, including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). TAMs and TANs exhibit a spectrum of functional phenotypes ranging from immunosuppressive that promote tumor growth, to pro-inflammatory that unleash anti-tumor immunity. Therapies that shift the inhibitory myeloid cell phenotypes toward more pro-inflammatory function are expected to positively impact anti-tumor immune responses and convert checkpoint inhibitor (CPIs)-resistant tumors into CPI-sensitive tumors. TREM1 (triggering receptor expressed on myeloid cells-1) is a transmembrane protein enriched in myeloid cells, including intratumoral TAMs, TANs and MDSCs. In a number of tumor types, TREM1 expression negatively correlated with patient survival. Furthermore, a survey of the immune infiltrates in a variety of human solid tumor types by flow cytometry and gene expression analysis revealed a high frequency of intratumoral TREM1+ myeloid cells in all tested tumors. We developed anti-human and anti-mouse TREM1 monoclonal antibodies (mAbs), termed PY159 and PY159m, respectively, to target TREM1+ myeloid cells. These mAbs triggered signaling pathways downstream of TREM1 and induced a highly selective pro-inflammatory cytokine signature in ex vivo assays. Additionally, PY159 treatment increased the myeloid cell expression of HLA-DR and the costimulatory molecule CD40, indicating an enhanced potential for costimulation and immune activation. Consistent with ex vivo results, in vivo treatment with PY159m promoted both innate and adaptive immune pathways in syngeneic mouse tumors revealed by gene expression profiling. These findings suggest that anti-TREM1 therapy re-educates TREM1+ myeloid cells into pro-inflammatory cells. Furthermore, PY159m was sufficient to drive anti-tumor activity as a single agent in a number of syngeneic tumor models. Strikingly, PY159m also converted anti-PD-1 mAb-resistant tumors into treatment-sensitive tumors with combination therapy, demonstrating the utility of targeting TREM1+ myeloid cells as a combination approach to improve CPI therapy responses. Mice cured of their tumors by PY159m/PD-1 mAb combination therapy were resistant to tumor re-challenge, demonstrating that targeting TREM1+ myeloid cells also supports adaptive immunity and induces long-term immunological memory. Based on these preclinical findings, we are developing PY159 as a therapeutic agent for monotherapy and/or CPI combination therapy for solid tumors.
Citation Format: Vladi Juric, Chris Chan, Erin Mayes, Manith Norng, Tiep Le, Subhadra Dash, Venkataraman Sriram, Erick Lu, Joshua L. Pollack, Mikhail Binnewies, Joanna Waszczuk, Xiaoyan Du, Shilpa Mankikar, Aritra Pal, Kevin P. Baker, Linda Liang. Targeting of TREM1+ myeloid cells to promote antitumor immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C105. doi:10.1158/1535-7163.TARG-19-C105