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Annual Review of Cancer Biology

Volume 6, 2022

Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade

Abstract

Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8+ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models,potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs.

Keyword(s): checkpoint inhibitors, immunoresistance, interferon-γ, JAK, major histocompatibility complex, tumor microenvironment
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/content/journals/10.1146/annurev-cancerbio-070220-111016
2022-04-11
2024-04-20
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Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade
Annual Review of Cancer Biology 6, 85 (2022); https://doi.org/10.1146/annurev-cancerbio-070220-111016
/content/journals/10.1146/annurev-cancerbio-070220-111016
/content/journals/10.1146/annurev-cancerbio-070220-111016
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  • Article Type: Review Article

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