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Tumor Microenvironment Remodeling by 4-Methylumbelliferone Boosts the Antitumor Effect of Combined Immunotherapy in Murine Colorectal Carcinoma

Abstract

We have previously demonstrated that a low dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment (TME) and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure (TIP). As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tumor growth. Importantly, we observed complete tumor regression in 75% of mice when 4Mu was administrated in combination with Cy+AdIL-12. The triple combination 4Mu+Cy+AdIL-12 also induced a shift toward antiangiogenic factors production in tumor milieu. Our results showed that TME remodeling is an interesting strategy to increase the efficacy of anticancer immunotherapies based on gene and/or cell therapy.

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References
1.
Ropponen K, Tammi M, Parkkinen J, Eskelinen M, Tammi R, Lipponen P . Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res. 1998; 58(2):342-7. View

2.
Toole B . Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004; 4(7):528-39. DOI: 10.1038/nrc1391. View

3.
Balkwill F, Capasso M, Hagemann T . The tumor microenvironment at a glance. J Cell Sci. 2013; 125(Pt 23):5591-6. DOI: 10.1242/jcs.116392. View

4.
Taghian A, Abi-Raad R, Assaad S, Casty A, Ancukiewicz M, Yeh E . Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol. 2005; 23(9):1951-61. DOI: 10.1200/JCO.2005.08.119. View

5.
Heldin C, Rubin K, Pietras K, Ostman A . High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004; 4(10):806-13. DOI: 10.1038/nrc1456. View