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

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 beta 2-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 up- regulated by interferon-gamma (IFN gamma) in a manner that depends on IFN gamma receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFN gamma 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.

Automated summary

Resistance to immunotherapy is often caused by acquired stealth mechanisms of tumor cells, such as loss of MHC class I expression or downregulation of antigen presentation pathways. Mutations in molecules involved in interferon-gamma signaling lead to unresponsiveness to IFN gamma and loss of recognition and killing by cytotoxic T lymphocytes. However, this mechanism also increases the sensitivity of tumor cells to natural killer cells, which could be exploited to overcome resistance.