A novel immunochemotherapy based on targeting of cyclooxygenase and induction of immunogenic cell death.

Affiliation

Huang H(1), Huang Y(1), Chen Y(1), Luo Z(1), Zhang Z(1), Sun R(2), Wan Z(1), Sun J(1), Lu B(2), Zhang L(3), Hu J(3), Li S(4).
Author information:
(1)Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
(2)Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
(3)UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
(4)Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA. Electronic address: [Email]

Abstract

Cyclooxygenase (COX) plays a crucial role in the "inflammogenesis of cancer", which leads to tumor progression, metastasis, and immunotherapy resistance. Therefore, reducing "inflammogenesis" by COX inhibition may be a key perspective for cancer therapy. However, the role of tumor-derived COX in the actions of COX inhibitors remains incompletely understood. In this study, applying "old drug new tricks" to repurpose 5-aminosalicylic acid (5-ASA), a COX inhibitor, we examined the effect of 5-ASA, alone or in combination with doxorubicin (DOX), in several cancer cell lines with different levels of COX expression. To facilitate the evaluation of the combination effect on tumors in vivo, a new micellar carrier based on PEG-b-PNHS polymer-conjugated 5-ASA (PASA) was developed to enhance codelivery of 5-ASA and DOX. Folate was also introduced to the polymer (folate-PEG-NH2-conjugated PASA (FASA)) to further improve delivery to tumors via targeting both tumor cells and tumor macrophages. An unprecedented high DOX loading capacity of 42.28% was achieved through various mechanisms of carrier/drug interactions. FASA was highly effective in targeting to and in inhibiting the growth of both 4T1.2 and CT26 tumors in BALB/c mice. However, FASA was more effective in CT26 tumor that has a high level of COX expression. Codelivery of DOX via PASA and FASA led to a further improvement in antitumor activity. Mechanistic studies suggest that inhibition of COX in vivo led to a more active tumor immune microenvironment. Interestingly, treatment with FASA led to upregulation of PD-1 on T cells, likely due to repressing the inhibitory effect of prostaglandin E2 (PGE2) on PD-1 expression on T cells. Combination of FASA/DOX with anti-PD-1 antibody led to a drastic improvement in the overall antitumor activity including regression of some established tumors at a suboptimal dose of FASA/DOX. Our data suggest that FASA/DOX may represent a new and effective immunochemotherapy for various types of cancers, particularly those cancers with high levels of COX expression.