Galectin-3 as a new negative checkpoint of the immune response is the key target for effective immunotherapy against prostate cancer

Abstract

Keywords: Active immunotherapy; combined treatment; preclinical model; drug new effect.Galectin-3 is the key immunological check-point responsible of the failure of immunotherapies protocols against prostate cancer and could be controlled by Docetaxelbased chemotherapy prior to vaccination. AbstractProstate cancer (PCa) is a major health problem worldwide. Taxol derivatives-based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status. In the case of immunotherapy, tumors develop robust immune escape mechanisms that abolish any protective response. However, Docetaxel has been shown to enhance the effectiveness of immunotherapy in a variety of cancers, but to date, the mechanism is still unknown. Herein, we showed first that Galectin-3 (Gal-3) expressed by prostate tumor cells is the principal immunological checkpoint responsible of the failure of immunotherapy; and that Docetaxel leads to the inhibition of Gal-3 expression in PCa cells as well as in clinical samples of mCRPC patients promoting a Th1 response. We thus optimized a prostate cancer animal model that undergoes surgical resection of the tumor like prostatectomy to mimic what is usually performed in patients. More importantly, using low and nontoxic doses of taxane prior to immunotherapy, we were able to directly impact the activation and proliferation of CD8+ cytotoxic T cells through reducing the number of CD8+CD122+CD28-T cells and highly control tumor recurrence. Thus, Gal-3 expression by PCa cells is a key inhibitor for the success of immunotherapy, and low doses of Docetaxel with noncytotoxic effect on leukocyte survival should be used prior to vaccination for all PCa patients. This combined treatment sequence right after surgery would promote the preconditioning of the tumor microenvironment, allowing for effective anti-tumor immunotherapy and can be transferred rapidly to clinical therapeutic protocols.

Galectins as Checkpoints of the Immune System in Cancers, Their Clinical Relevance, and Implication in Clinical Trials

“…Moreover, we recently demonstrated the essential role of Gal-3 in the establishment of immune tolerance in a mouse prostate cancer model. We showed that the specific targeting of this particular galectin in tumor cells is enough to render the vaccine immunotherapy efficient, with long-term protection against cancer recurrence [119]. These results highlight Gal-3 as an excellent prognosis marker for immunotherapy responders and a potential target when combined with a therapeutic vaccine to benefit prostate and other Gal-3-dependent cancer patients.…”

“…Several ongoing or already terminated clinical trials with anti-ICP therapy show prostate cancer as a highly refractory disease for this kind of therapy. Recently, we suggest that the inhibition Gal-3 expressed by the tumor cells promotes strong and long-term immune protective response after tumor resection and vaccination of the animals [119]. Supporting these results, a phase Ib clinical trial (#NCT02117362) combining GR-MD-02 and Ipilimumab (anti-CTLA-4) shows no adverse effects identified owing to GR-MD-02, suggesting that Gal-3 targeting per se does not cause any clinical problem (from Providence Cancer Center and Galectin Therapeutics communications).…”

Molecular regulation of prostate cancer by Galectin-3 and estrogen receptor

“…Emerging studies are associating the expression of the Galectin-3 with the immune response against prostate cancer, as well as to the success of effective immunotherapy. Tiraboschi et al (48) showed that when Galectin-3 is expressed by prostate tumor cells, it can control the tumor growth and decrease the number of tumor infiltrated T cells, suggesting that this protein is the principal immunological checkpoint responsible of the failure of immunotherapy in advanced prostate cancer. In addition, low doses of docetaxel inhibited the expression of the Galectin-3 in prostate cancer cells as well as in clinical samples of patients with metastatic cancer and CRPC, controlling tumor recurrence by increasing proliferation and infiltration of CD8+ cytotoxic T (49).…”