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Review
. 2022 Jan;19(1):23-32.
doi: 10.1038/s41423-021-00735-3. Epub 2021 Aug 12.

IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

Wan Du  1   2 , Timothy L Frankel  1 , Michael Green  2   3   4   5 , Weiping Zou  6   7   8   9   10
Affiliations
Review

IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

Wan Du et al. Cell Mol Immunol. 2022 Jan.

Abstract

The majority of colorectal cancer patients are not responsive to immune checkpoint blockade (ICB). The interferon gamma (IFNγ) signaling pathway drives spontaneous and ICB-induced antitumor immunity. In this review, we summarize recent advances in the epigenetic, genetic, and functional integrity of the IFNγ signaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB. Moreover, we discuss how to target IFNγ signaling to inform novel clinical trials to treat patients with colorectal cancer.

Keywords: ARID1A; Apoptosis; Colorectal cancer; EZH2; Ferroptosis; IFNGR; Immunity; Interferon; MHC; PD-1; PD-L1; Palmitoylation; T cell.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
IFNγ signaling pathway genes. IFNγ binds to the IFNγ receptor (IFNGR) complex, recruiting JAK1 and JAK2 to the receptor complex and inducing the subsequent phosphorylation of STAT1. Then, phosphorylated STAT1 dimers translocate to the nucleus and induce the transcription of ISGs (interferon-stimulated genes) by binding GAS (IFN gamma-activated sequences) in the gene promotors. The IFNγ signaling pathway can be regulated at the epigenetic, transcriptional, posttranscriptional, and posttranslational levels
Fig. 2
Fig. 2
Cross-talk between PRC2 and SWI/SNF complexes in regulating the IFNγ signaling pathway and tumor immunity. The PRC2 component EZH2 represses IFNγ signaling genes (CXCL9 and CXCL10), diminishing effector T-cell tumor trafficking. The SWI/SNF complex core member ARID1A antagonizes EZH2 and enhances IFNγ signaling gene expression, promoting T-cell tumor migration and antitumor immunity. Targeting PRC2 and SWI/SNF complexes may potentiate ICB therapy
Fig. 3
Fig. 3
Lysosomal sorting and degradation of palmitoylated IFNGR1. AP3D1 recognizes the palmitoylation signal and then binds and sorts palmitoylated IFNGR1 to lysosomes for degradation. Optineurin competes with AP3D1 for IFNGR1 binding and prevents IFNGR1 lysosomal sorting and degradation. The loss of optineurin impairs the integrity of the IFNγ signaling pathway in colorectal cancer. Low (left) and high (right) optineurin expression
Fig. 4
Fig. 4
Dual effects of IFNγ in cancer immunity. IFNγ exerts antitumor effects via multiple mechanisms. In contrast, IFNγ can protect cancer cells from immune cell attack by inducing PD-L1, IDO, and arginase expression. Chronic IFNγ signaling enforces immunosuppressive mechanisms in the tumor microenvironment
Fig. 5
Fig. 5
Mode of tumor cell death induced by T cells. Antigen-presenting cells (APCs) prime and activate T cells. T cells can induce tumor cell apoptosis by secreting perforin and granzymes. In addition, T cells promote tumor cell ferroptosis via IFNγ-mediated downregulation of SLC3A2 and SLC7A11
Fig. 6
Fig. 6
Targeting the IFNγ signaling pathway in colorectal cancer therapy. Targeting EZH2 (enhancer of zeste homolog 2), DNMTs (DNA methyltransferases), TET (ten–eleven translocation family of protein 2), and palmitoylation can rescue and stimulate the expression of key IFNγ signaling genes and enhance antigen presentation, T-cell activation, and T-cell trafficking in colorectal cancer
See this image and copyright information in PMC

References

    1. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64. - PubMed
    1. André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383:2207–18. - PubMed
    1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20. - PMC - PubMed
    1. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13. - PMC - PubMed
    1. Pitt JM, Vétizou M, Daillère R, Roberti MP, Yamazaki T, Routy B, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and-extrinsic factors. Immunity. 2016;44:1255–69. - PubMed

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