Title:HPMA Copolymer-Bound Doxorubicin Induces Immunogenic Tumor Cell Death
Volume: 20
Issue: 38
Author(s): M. Sirova, M. Kabesova, L. Kovar, T. Etrych, J. Strohalm, K. Ulbrich and B. Rihova
Affiliation:
Keywords:
Anti-tumor immune response, calreticulin, heat shock proteins, HMGB1, HPMA-based doxorubicin delivery, targeted
cytotoxic drugs.
Abstract: Treatment of murine EL4 T cell lymphoma with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer
conjugates of doxorubicin (Dox) leads to complete tumor regression and to the development of therapy-dependent longlasting
cancer resistance. This phenomenon occurs with two types of Dox conjugates tested, despite differences in the covalent
linkage of Dox to the polymer carrier. Such a cancer resistance cannot fully express in conventional treatment with
free Dox, due to substantial immunotoxicity of the treatment, which was not observed in the polymer conjugates. In this
study, calreticulin (CRT) translocation and high mobility group box-1 protein (HMGB1) release was observed in EL4
cells treated with a conjugate releasing Dox by a pH-dependent manner. As a result, the treated tumor cells were engulfed
by dendritic cells (DC) in vitro, and induced their expression of CD80, CD86, and MHC II maturation markers. Conjugates
with Dox bound via an amide bond only increased translocation of HSPs to the membrane, which led to an elevated
phagocytosis but was not sufficient to induce increase of the maturation markers on DCs in vitro. Both types of conjugates
induced engulfment of the target tumor cells in vivo, that was more intense than that seen with free Dox. It means that the
induction of anti-tumor immunity documented upon treatment of EL4 lymphoma with HPMA-bound Dox conjugates does
not rely solely on CRT-mediated cell death, but involves multiple mechanisms.
