| dc.description.abstract | Prostate cancer (PCa) is the third leading cause of cancer death. The lack of an effective cure for advanced stages and an overall low response to immunotherapy give prominence to the critical need for developing novel therapies. PCa has an “immune cold” tumor microenvironment (TME), suggesting that immunotherapy can be enhanced by converting the immune “cold” TME to immune “hot” TME, which will be at the front lines to overcome immune evasion in PCa. Understanding the mechanism of PCa progression and TME remodeling will be essential to change the unfavorable TME and develop new therapeutic strategies.
To meet the challenges of bio-molecular synthesis for fast growth, cancer cells reprogram their metabolism to derive energy to aerobic glycolysis, and such reprograming usually results from a composite consequence of genetic and environmental changes. This includes the depletion of glucose and the accumulation of tumor-derived lactate. Together with the secretion of immunosuppressive cytokines, these contribute to establishing an immune “cold” TME, suggesting that suppression of metabolic reprogramming in cancer cells can be an effective way to inhibit immune evasion. However, as aerobic glycolysis and oxidative phosphorylation (OXPHOS) are also needed for T cell activation and function, general metabolic inhibitors directly targeting metabolism can disrupt hemostasis in T cells as well, and thus will not be effective for changing the immune “cold” tumors. A new cancer cell specific suppression of aerobic glycolysis without inhibiting T cell metabolism is needed to improve the PCa immunotherapy.
In this study, we report that deletion of ectopic FGFR1 signaling reduced aerobic glycolysis and promoted OXPHOS in PCa cells, suggesting a reversal of PCa metabolic reprogramming. Since normal T cells do not express FGFR1, it is expected that suppression of FGFR1 signaling can be a normal strategy to selectively target aerobic glycolysis in PCa cells to improve PCa immunotherapy. We found that conditioned medium from PCa cells suppressed T cell growth in vitro, potentially through tumor-derived cytokines and metabolites secreted. We observed blunting ectopic FGFR1 signaling either by inactivating FGFR1 gene or by treating with FGFR tyrosine kinase inhibitor increased CD3⁺CD8⁺ T cells in the TRAMP PCa model, indicating that inactivating ectopic FGFR1 signaling facilitates penetration of T cells to the tumor. Moreover, this T-cell mediated immune response can be boosted by treating with anti-immune checkpoint antibody, anti-PD-1 antibody. In addition, bioinformatics analysis of the public database of the single-cell RNA sequence of human PCa revealed that the tumor with FGFR1 expression in epithelial cells was associated with a high CD8α⁺ T cell population, suggesting that high FGFR1 expression in epithelial cells suppressed infiltration of CD8α⁺ T cells, which is consistent with our data derived from PCa cell and mouse models.
Together, the data suggest that the combination of FGFR1 inhibitor and anti-checkpoint treatment can be an effective way to increase CD8⁺ T cell-mediated immune response in prostate tumors, and therefore, reveals a novel strategy for PCa treatment. | |
