Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell’s metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.
immunohistochemistry. Paraffin sections were stained with hematoxylin and eosin (H&E) or Ki67 according to standard methods. For immunohistochemistry, cryosections were stained overnight at 4°C with fluorescent antibodies. Results H&E images confirmed that transgenic Apc 1322T mice lacking IL-25 had smaller tumours and showed less dysplasia than Apc 1322T mice with normal IL-25 expression. Ki67 staining showed that tumours express higher Ki67 levels than adjacent normal intestinal tissue. The tumour-associated tertiary lymphoid structures (TATLS) of Apc 1322T mice lacking IL-25 appeared larger, indicating a more robust anti-tumour immune response.Likewise, Apc 1322T mice lacking ILC2s had smaller, less dysplastic tumours. TATLS in these mice were bigger than mice with ILC2s but smaller than Apc 1322T mice lacking IL-25, indicating that IL-25 may act via additional protumourigenic cell types.Immunohistochemistry confirmed the presence of ILC2s, as well as MDSCs the tumours of Apc 1322T mice, suggesting that these cells create an immunosuppressive niche. Conclusions This pilot study confirms that genetic ablation of either IL-25 or ILC2s promotes anti-tumour immune reactions and decreases tumour size, correlating with reduced intestinal tumour proliferative capacity and dysplasia. Mice lacking IL-25 or ILC2s had larger TATLS, which are known to be associated with improved prognosis in patients. This study, along with previous data, highlights the potential therapeutic benefit of targeting the IL-25-ILC2 axis for colorectal cancer. Further studies are required to bring this from bench to bedside.
Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral and non-viral etiologies. Immune checkpoint blockade primarily benefits patients with viral HCC. Expansion of suppressive myeloid cells is a hallmark of chronic inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance in the steatohepatitis setting. Here, we present a high resolution atlas of hepatic innate immune cells from patients with HCC that unravels a steatohepatitis contexture characterized by the emergence of high entropy myeloid cell states and myeloid-biased NK cell differentiation. We identify a discrete population of tumor-infiltrating myeloid cells, predominant in the steatohepatitis setting, that expresses a variety of myeloid lineage-affiliated genes, including granulocyte, macrophage and dendritic cell features, and can be identified in HCC tumors based on selective dual expression of TREM1 and CD163. Functional characterization reveals that TREM1+ CD163+ myeloid cells highly express TGF-beta and IL-13RA, localize to HCC fibrotic lesions, and potently suppress T cell effector functions ex vivo, a function further potentiated by TREM1 engagement. We refer to this population as TREM1+ regulatory myeloid cells (TREM1+ Mreg). Deconvolution analyses in large cohorts of patients with HCC and other solid tumors reveals that the density of TREM1+ Mreg increases in advanced stages, associates with poor prognosis, and therapeutic resistance to PD-1 blockade. Our data support myeloid subset-targeted immunotherapies to treat HCC and identify TREM1 as a therapeutic target.
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