Mutations Associated with Acquired Resistance to PD-1 Blockade
T cells were no longer able to exert their cytotoxic activity, because of either a lack of tumor antigen recognition and activation or a loss of sensitivity to their effector molecules by the cancer cells. The general possibilities are loss of mutational or shared tumor antigens that are recognized by T cells, loss of antigen-presenting machinery components (e.g., beta-2-microglobulin and HLA),12-14 tumor-cell–induced or myeloid-cell–induced inactivation of T-cell signaling,32,33 or insensitivity to the proapoptotic effects of toxic granules (e.g., perforin and granzymes), death receptors (e.g., Fas and tumor necrosis factor–related apoptosis-inducing ligand [TRAIL]), or interferons.
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