LOW DOSES OF DOCETAXEL PRIOR TO IMMUNOTHERAPY LEAD TO PROSTATE TUMOR-FREE OUTCOME THROUGH GALECTIN-3 NEGATIVE REGULATION.

CORAPI, ENRIQUE; CHAUCHEREAU, ANNE; GENTILINI, LUCAS; VELAZQUEZ, CARLA; COMPAGNO, DANIEL; TIRABOSCHI, CAROLINA; JAWORSKI, FELIPE M; LADERACH, DIEGO J

Congreso; REUNIÓN ANUAL DE SOCIEDADES DE BIOCIENCIA 2019; 2019

SAIC

Based on animal model results and the analysis of clinical data from metastatic and castration resistant prostate cancer (mCRPC) patients, we were able to demonstrate the advantages and the mechanisms by which Docetaxel (DTX)-based chemotherapy induces the correct pre-conditioning of the tumour microenvironment to allow high cytotoxic T cell activity to avoid prostate tumour growth and recurrence. First, analysis of the gene expression of human PCa cells showed that treatment with DTX decreases the expression of Galectin 3 (Gal-3) in either chemo-sensitive or -resistant prostate cancer (PCa) cell lines (98 ± 3 %) but also in clinical samples of mCRPC patients treated by taxane-based chemotherapy (79 ± 17 %). To evaluate whether this DTX-dependent Gal-3 downregulation in PCa tumors could be one of the principal molecular factors responsible for chemotherapy enhancement of immunotherapy, we decide to inoculate mice with an autologous BM-DC vaccine loaded with lysates from TRAMP-C1 (TC1) cells pretreated by DTX in vitro or expressing an anti-Gal-3 shRNA. This immunotherapy protocol completely protects the animals to the growth of Gal-3 deficient-PCa tumors, and suggests that Gal-3 expressed by the tumor could be one of the major negative checkpoints of the immune response against PCa. We finally clearly demonstrate that a low doses DTX treatment decreasing gal-3 expression in tumor prior vaccination protects 6/7 treated mice for prostate cancer recurrence and metastasis development in mice after primary tumor-resection. In conclusion, our results strongly suggest that Gal-3 is one of the principal immunosuppressor in prostate cancer that limits the success of immunotherapy. Finally, we show that low doses of DTX-based chemotherapy would promote a decrease of Gal-3 expression by the tumors to create a permissive tumor microenvironment for successful immunotherapy, which in turn could control tumor recurrence for all PCa patients.