Dataset Information

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models.

ABSTRACT: Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti-PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti-PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti-PD-L1, increased the percentage of tumor-infiltrating CD8(+) T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity.

SUBMITTER: Rios-Doria J

PROVIDER: S-EPMC4674486 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models.

Rios-Doria Jonathan J Durham Nicholas N Wetzel Leslie L Rothstein Raymond R Chesebrough Jon J Holoweckyj Nicholas N Zhao Wei W Leow Ching Ching CC Hollingsworth Robert R

Neoplasia (New York, N.Y.) 20150801 8

Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti-PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti-PD-1 and CTLA-4 mA ...[more]

PMID: 26408258

Similar Datasets

Project description:Simple Summary In addition to cancer cells themselves, tumors consist of several cell types that either function to suppress or promote tumor growth and disease progression. Macrophages are amongst the most abundant of these cell types and possess contrasting abilities to either enhance tumor growth and spread or to destroy cancer cells. Anti-cancer therapeutics such as Rituximab, Herceptin and Cetuximab, are cornerstones of current treatment for cancer patients. These therapeutics are antibodies that directly bind to cancer cells and aid macrophages in detecting and destroying these cells, through a process known as antibody dependent cellular phagocytosis (ADCP). Although the use of anti-cancer antibodies to treat large established tumors has improved survival rates, significant numbers of patients do not respond to this type of therapy. Thus, recently there has been an intense focus on designing new therapies which alter macrophages inside tumors, so that they can more effectively eliminate cancer cells through ADCP. Several molecules on the surface of macrophages can be targeted with antibodies to improve their ability to recognize and eliminate cancer cells. Here we review the most promising of these new targets, which offer the potential to circumvent resistance to therapy in cancer patients. Abstract Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through the process of antibody-dependent cellular phagocytosis (ADCP). Clinically important tumor-targeting monoclonal antibodies (mAb) such as Rituximab, Herceptin and Cetuximab, function, at least in part, by inducing macrophages to eliminate tumor cells via ADCP. For IgG mAb, this is mediated by antibody-binding activating Fc gamma receptors (FcγR), with resultant phagocytic activity impacted by the level of co-engagement with the single inhibitory FcγRIIb. Approaches to enhance ADCP in the tumor microenvironment include the repolarization of TAMs to proinflammatory phenotypes or the direct augmentation of ADCP by targeting so-called ‘phagocytosis checkpoints’. Here we review the most promising new strategies targeting the cell surface molecules present on TAMs, which include the inhibition of ‘don’t eat me signals’ or targeting immunostimulatory pathways with agonistic mAb and small molecules to augment tumor-targeting mAb immunotherapies and overcome therapeutic resistance.

Dataset Information

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models.

Publications

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets