Insights into the mechanisms of alternative macrophage polarization to circumvent cancer immunotherapy resistance

Tumor-associated-macrophages (TAMs) play a pivotal role in promoting tumor progression and therapy resistance; their targeting has recently emerged as a promising strategy for cancer defeat. Current approaches focus on reprogramming TAMs from the M2 pro-tumoral to the M1 anti-tumoral phenotype to kill cancer cells. Unfortunately, in-depth knowledge of TAMs and a signature that can reliably identify them still needs to be improved. We identified a splicing isoform of the FKBP5 gene, FKBP51s, exploited by cancer cells to suppress undesired immunity and highly expressed in circulating monocytes of cancer patients resistant to immunotherapy. Aim of this study is to decipher the role of FKBP51s in TAM biology to identify new potential therapeutic targets to their reprogramming. Alternative-macrophage polarization showed typical features of M2 and M1, such as STAT1 downregulation in favor of STAT3/6, and a shift towards arginase 1 metabolism and scavenger receptors expression. Interestingly, FKBP51s levels strongly increased in M2-macrophages, thus suggesting that FKBP5 alternative splicing occurs in TAMs. FKBP51s silencing restored STAT1 activity, increased the secretion of pro-inflammatory cytokines, while impairing the anti-inflammatory cytokines. The depletion of the splice isoform also impacted on TAMs migration, invasiveness, and T-cells proliferation. Finally, silencing of FKBP51s also impaired OXPHOS, typical of M2 macrophages, and restored the glycolytic activity, an M1 feature. Results from this study suggest a relevant role for FKBP51s in promoting the pro-tumoral activities of TAMs and highlight this splice isoform as a new potential therapeutic target to reprogram TAMs towards an anti-tumoral macrophage phenotype, thus overcoming the immune suppressive tumor microenvironment.