Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer mortality with a dismal 2–5% 5-year survival rate. Monotherapy with Gemcitabine has limited success, highlighting the need for additional therapies that enhance the efficacy of current treatments. We evaluated the combination of Gemcitabine and Rosiglitazone, an FDA-approved drug for the treatment of type II diabetes, in an immunocompetent transplantable mouse model of pancreatic cancer. Tumor progression, survival and metastases were evaluated in immunocompetent mice with subcutaneous or orthotopic pancreatic tumors treated with Pioglitazone, Rosiglitazone, Gemcitabine or combinations of these. We characterized the impact of high dose Rosiglitazone and Gemcitabine therapy on immune suppressive mediators, including MDSC and T regulatory cells, and on modulation of peripheral and intra-tumoral T cell populations. Combinations of Rosiglitazone and Gemcitabine significantly reduced tumor progression and metastases, enhanced apoptosis, and significantly extended overall survival compared to Gemcitabine alone. Rosiglitazone altered tumor-associated immune suppressive mediators by limiting early MDSC accumulation and intra-tumoral T regulatory cells. Combination therapy with Rosiglitazone and Gemcitable modulated T cell populations by enhancing circulating CD8+ T cells and intra-tumoral D4+ and CD8+ T cells while limiting T regulatory cells. The results suggest that Rosiglitazone, in combination with Gemcitabine, decreases immune suppressive mechanisms in immunocompetent animals and provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic cancer.

Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells

“…These data are in accordance with earlier works performed in the subcutaneous model of PDAC. 25,26 Interestingly, we found for the first time that tumor progression was accompanied by an enrichment of granulocytic MDSC but simultaneously by a decrease in the frequency of monocytic MDSC. In different tumor models, the proportion of granulocytic and monocytic MDSC subsets is highly variable and depends on factors that have not yet been well investigated.…”

“…13,25,26 Using an orthotopic Panc02 model of murine PDAC, we revealed a strong accumulation of both immunosuppressive monocytic and granulocytic subpopulations of MDSC in the tumor microenvironment and lymphatic organs. These data are in accordance with earlier works performed in the subcutaneous model of PDAC.…”

“…25 Another approach represents the usage of the chemotherapeutic drug gemcitabine alone or in combination with other chemotherapeutics or with immunotherapy. This approach has also been 15,26 It has been shown that phosphodiesterase (PDE)-5 inhibitors sildenafil and tadalafil, which are used for the treatment of erectile dysfunction, pulmonary hypertension, and cardiac hypertrophy, 29 can exert antitumor effects in various implantation tumor mouse models by abrogating MDSC functions associated with the T cell accumulation and activation. 30,31 We have recently reported that sildenafil reduced the amount of chronic inflammatory factors (IL-1b, VEGF, and GM-CSF) and inhibited immunosuppressive MDSC functions, which led to the restoration of the T cell antitumor reactivity and to a significantly prolonged survival of treated mice.…”

Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4-difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells

“…Pancreatic cancer is one of the most deadly malignancies among all types of cancers with a five-year survival rate of less than 6% in the United States [2,3]. Successful translation of potential cancer therapies into clinics will mainly depend on targeted drug delivery approaches with high safety margin.…”

CAR T-Cell Therapy: The Role of Physical Barriers and Immunosuppression in Lymphoma

“…Several studies have shown that patients treated with gemcitabine had significantly lower levels of the immunosuppressive molecule TGFb, Tregs, and MDSCs but an increased number of DCs, monocytes, and activated T-cells. 46,47 CLL is commonly treated with fludarabine, bendamustine, and lenalidomide. 48 While both fludarabine and bendamustine are immunosuppressive per se, lenalidomide enhances the degradation of Ikaros 1 and 3.…”