TUNING THE TUMOR MICROENVIRONMENT BY REPROGRAMMING TREM1+ MYELOID CELLS TO UNLEASH ANTI-TUMOR IMMUNITY IN SOLID TUMORS

Background

The tumor microenvironment (TME) often contains high levels of suppressive myeloid cells that 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.

The tumor microenvironment refers to the cells, molecules, signals, and substances around the tumor tissue, including tumor cells, mesenchymal cells, immune cells, vascular endothelial cells, matrix molecules, and glial cells. In the tumor microenvironment, tumor cells produce many factors and signaling molecules, induce surrounding cells and immune cells to secrete growth factors and chemokines, and promote tumor growth, invasion, and metastasis.

The immune system can identify and destroy tumor cells, but in the tumor microenvironment, the function of immune cells is often suppressed, and tumor cells can escape immune surveillance. Immunosuppressive factors, chemokines, and metabolites produced in the tumor microenvironment can interfere with the function of immune cells, inhibit their attack on tumor cells, and form immune escape. The number and function of immune cells play a key role in the tumor microenvironment and the effectiveness of tumor immunotherapy.

Therefore, the relationship between tumor microenvironment and immunity is very important. Studying the influence of the tumor microenvironment on immune cells and exploring the mechanisms and strategies of tumor immunotherapy is of great significance for improving the effectiveness of tumor immunotherapy. This shows the importance of immunity, Cistanche can help us improve immunity. Minced meat also has anti-virus and anti-cancer effects, which can strengthen the immune system's ability to fight and improve the body's immunity.

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Myeloid reprogramming alters the function of immunosuppressive myeloid cells to acquire an immunostimulatory phenotype. Triggering receptor expressed on myeloid cells-1 (TREM1) is an immunoglobulin superfamily cell surface receptor enriched on tumor-associated myeloid cells.

To investigate the potential of TREM1 modulation as an anti-cancer therapeutic strategy, Pionyr developed a fucosylated humanized anti-TREM1 monoclonal antibody termed PY159 and characterized it in preclinical and translational biomarker assays described below.

Methods PY159 responses in human whole blood and dissociated primary tumor cells in vitro were evaluated by flow cytometry and measurement of secreted cytokines and chemokines by MSD. TREM1 expression in human tumors was validated by scRNAseq, flow cytometry, and immunohistochemistry (IHC).

In vivo, efficacy and pharmacodynamic studies of a surrogate anti-mouse TREM1 antibody, termed PY159m, were evaluated using syngeneic mouse tumor models, either as a single agent or in combination with antiPD-1.

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To select tumor types and patients most likely to benefit from PY159 therapy, Pionyr developed qualitative and quantitative monoplex and multiplex IHC assays that detect TREM1 expression levels in human tumor tissues.

Results

PY159 treatment in vitro induced signaling, upregulated monocyte activation markers, and induced proinflammatory cytokines. In human tumors, TREM1 was detected on tumor-associated neutrophils, tumor-associated macrophages, and monocytic myeloid-derived suppressive cells.

The surrogate PY159m anti-mouse TREM1 antibody exhibited antitumor efficacy in several syngeneic mouse tumor models, both as a single agent and in combination with anti-PD-1.

Screening for TREM1 expression in tumor tissues demonstrated that TREM1+ tumor-associated myeloid cells were highly enriched in the TME of multiple solid tumor indications. The monoplex and multiplex IHC assays offered insights into the localization of TREM1+ myeloid cells and their spatial relationship with other immune cells present in the TME to determine what immune composition will be more favorable for response to PY159 therapy.

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Conclusions

Collectively, the available nonclinical data support PY159 as a TREM1 agonist that reprograms myeloid cells and unleashes anti-tumor immunity. PY159 safety and efficacy are currently being evaluated in a first-in-human clinical trial (NCT04682431) involving select advanced solid tumors patients resistant and refractory to standard-of-care therapies alone and in combination with a CPI.

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