Highlights d TAM-expressed TREM2 is associated with T cell exhaustion and anti-PD-1 resistance d Effector-enhanced anti-TREM2 antibody treatment drives anti-tumor immunity d TAM abundance and suppression are reduced following anti-TREM2 therapy d Anti-TREM2 therapy potentiates T cell activation and response to anti-PD-1 treatment

The purpose of this study was to investigate a prognostic indicator that can differentiate node negative breast cancer patients (N = 39, T2N0M0) with high risk and low risk for the development of recurrence or metastases. Preoperative plasma prolactin (PRL) was estimated by radioimmunoassay. The expression of PRL, p53, nm23, and c‐erbB2 was investigated by immunohistochemical (IHC) localization; cathepsin D (CD, Enzyme Linked Sorbant Assay) and estrogen‐ and progesterone‐receptors (ER and PR, Dextran coated charcoal method) were estimated in the tumor cytosols. The follow‐up period was 2–6 years. Statistical comparisons were made between each marker for relapse‐free survival (RFS) and overall survival (OS). Of the 39 patients, 18 had hyperprolactinemia (PRL > 20.0 ng/ml plasma), whereas overexpression of p53 was observed in 55% (17/31) tumors. These were independently and in combination associated with a reduced RFS and OS. The rest of the investigated markers did not show promising results. Hyperprolactinemia and/or overexpression of p53 were associated with aggressiveness of the tumor, early disease relapse or metastases, and poor OS in patients with node negative breast cancer. These two markers may enhance our ability to identify node negative breast cancer patients with aggressive tumors, for whom the use of adjuvant chemo and/or endocrine therapy is unequivocally justified. © 1996 Wiley‐Liss, Inc.

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The tumor microenvironment (TME) often contains high levels of suppressive myeloid cells that may contribute to innate checkpoint inhibitor (CPI) resistance. Pionyr's Myeloid Tuning approach involves altering the composition and/or the function of myeloid cells in the TME. To this end, therapeutic targeting of tumor-associated macrophages (TAMs) is a promising strategy to increase CPI response rates in solid tumor indications, as well as to overcome resistance to CPI therapies. Pionyr and others identified the transmembrane protein triggering receptor expressed on myeloid cells-2 (TREM2) as a highly enriched TAMs target. Furthermore, TREM2 mRNA expression negatively correlates with patient survival in a variety of tumor types, supporting the involvement of TAMs in tumor progression. Pionyr developed a lead anti-TREM2 monoclonal antibody (mAb), termed PY314, as well as a murinized version of PY314, termed PY314m. PY314m demonstrated significant anti-tumor activity either as single agent in CPI-sensitive syngeneic tumor models or in combination with anti-PD-1 in CPI-resistant syngeneic tumor models. Mechanistically, PY314m reduced the pro-tumorigenic MHC class II-low, M2-like TAMs, induced pro-inflammatory cytokine production, significant increased CD8+ T cell infiltration into the TME. These findings suggest that PY314 therapy could be used to overcome CPI resistance in humans. To select patients most likely to benefit from PY314 therapy, Pionyr developed a qualitative IHC assay that detects TREM2 expression levels in formalin-fixed, paraffin-embedded human tumor tissues. Screening for TREM2 expression in tumor tissues demonstrated that TREM2+ TAMs were present in multiple solid tumor indications and their number increased with disease grade in a selected set of indications. Ongoing efforts are aimed at better understanding localization of TREM2+ TAMs within the TME, and spatial relationship of the TREM2+ TAMs to other immune cells present in the TME. The TREM2 IHC assay will be used to test our hypothesis that patients with tumors with high level of TREM2+ TAMs are most likely to benefit from PY314 treatment. Citation Format: Nadine S. Jahchan, Mikhail Binnewies, Joshua L. Pollack, Ranna Mehta, Subhadra Dash, Christine Tun, Erick Lu, Xiaoyan Du, Kevin P. Baker, Len Reyno, Venkataraman Sriram. Tuning the tumor myeloid microenvironment (TME) by targeting TREM2+ tumor-associated macrophages to overcome resistance to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB071.