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

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