Resistance to immunotherapy: clouds in a bright sky

Two major challenges persist for an optimal management of immunotherapy: i) identifying those patients who will benefit from this type of therapy, and ii) determining the biological, cellular and molecular mechanisms that trigger disease progression while on therapy. There is a consensual view in favor of standardizing practices currently used to measure programmed death ligand 1 (PD-L1) expression that relates to innate resistance. The tumor mutation landscape has been widely explored as a potential predictor of treatment efficacy. In contrast, our knowledge is rather limited as concerns the mechanisms sustaining acquired resistance to checkpoint blockade immunotherapy in patients under treatment. Upregulation of T cell immunoglobulin mucin domain 3 (TIM-3) in CD8+ T-cells has been reported in patients developing acquired resistance to anti-PD-1 treatment. Resistance mechanisms are even more complex for combinatorial strategies linking immunotherapeutic agents and conventional therapies, an area that is expanding rapidly. However, with the arrival of advanced analytical methods such as mass cytometry, there is reason for optimism. These methods can identify cellular mechanisms governing response to therapy and resistance. The clinical use of inhibitors of tumor-microenvironment-modulated pathways, such as those targeting indoleamine 2, 3-dioxygenase (IDO), hold promise for resistance management.