The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1β and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-inflammatory cytokines vary greatly depending on the cancer type. Here we discuss recent studies highlighting contrasting roles of the inflammasome pathway in curbing versus promoting tumorigenesis. On one hand, the inflammasomes participate in stimulating anti-tumor immunity, but they have also been shown to contribute to immunosuppression or to directly promote tumor cell survival, proliferation, and metastasis. A better understanding of inflammasome functions in different cancers is thus critical for the design of novel cancer immunotherapies.
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. REFERENCE 1. Jou E, et al. An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc mutation-driven intestinal tumorigenesis. Sci Immunol 2022 Jun 3;7(72):eabn0175.
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