Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer

ILC3s control airway inflammation by limiting T cell responses to allergens and microbes

“…To more directly examine how ILC3s in the MedLNs functionally impact adaptive immunity, we used a mouse model in which ILC3s selectively lack MHC class II by crossing Rorc cre mice and mice with floxed alleles of H2-Ab1 ( Goc et al, 2021 ; Hepworth et al, 2013 , 2015 ; Melo-Gonzalez et al, 2019 ). Following induction of HDM-induced airway inflammation, we identify that this mouse line significantly and selectively targets for MHC class II deletion only in ILC3s, and does not impact MHC class II levels on B cells, cDC subsets, macrophages (Macs), T cells, or ILC2s in the MedLN and lung parenchyma relative to littermate controls ( Figures 2D , 2E , S2A , and S2B ).…”

“…These cytokines drive antimicrobial responses that shape the microbiota and protect from invading pathogens ( Ouyang et al, 2008 ; Sonnenberg et al, 2011 ; Zheng et al, 2008 ). Furthermore, ILC3s are major regulators of immunological tolerance to the microbiota and dietary antigens in the intestine, in part through the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or IL-2 that subsequently support regulatory T cell (Treg) homeostasis ( Mortha et al, 2014 ; Zhou et al, 2019 ) or through direct regulation of CD4 + T cells by antigen presentation on major histocompatibility complex class II (MHC class II) ( Goc et al, 2021 ; Hepworth et al, 2013 , 2015 ; Melo-Gonzalez et al, 2019 ; Sonnenberg and Hepworth, 2019 ).…”

Immune Checkpoints and Innate Lymphoid Cells—New Avenues for Cancer Immunotherapy

“…The proportion of ILC subsets differs according to the organ [ 16 ]. ILC transcriptional profile, phenotype and function are heavily influenced by their microenvironment and their phenotypes vary largely from tissue to tissue [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Genetic fate-mapping in mouse using key ILC features has further confirmed that ILC exhibit substantial plasticity and can modify their phenotype and function to resemble other ILC subsets, depending on the microenvironment signals [ 23 , 24 , 25 , 26 ].…”

The Dual Role of Innate Lymphoid and Natural Killer Cells in Cancer. from Phenotype to Single-Cell Transcriptomics, Functions and Clinical Uses

“…Data from the literature show that these pro-inflammatory ILC1s derive from ILC3 transformation under the influence of TGF-β and IL-23 [102,103], which are abundant in CRC [104]. ILC3s in CRC were impaired in their frequencies and functions [105].…”

“…In addition, in CRC, during the tumor progression, the amount of NKp44 + ILC3s decreases with a concomitant increment in ILC1s and NKp44 − ILC3s [141], thus indicating ILC plasticity [101]; the reduction in NKp44 + ILC3s is also related to tertiary lymphoid structure reduction in CRC [141]. Another study on CRC reported not only an alteration of ILC3s in terms of frequency and plasticity, but also an imbalance with T cells; ILC3s were shown to be protective against CRC; however, their alteration leads to CRC invasion and resistance to immunotherapies because of microbiota changes [105]. In vivo studies demonstrated that in the gut the production of GM-CSF by ILC3s was driven by macrophages that produce IL-1β in response to microbial signals.…”