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Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells

Lookup NU author(s): Dr Henrique De Paula Lemos, Professor Andrew Mellor

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Abstract

In recent years, the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the present study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4+ T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelodepletion and leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum–resident calreticulin and extracellular release of high-mobility group box 1. Additionally, there was enhanced tumor Ag uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8+ T cells and, more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4+ T cells. Notably, the combination of melphalan and CD4+ T cell adoptive cell therapy was more efficacious than either treatment alone in prolonging the survival of mice with advanced B cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan’s immunostimulatory effects and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4+ T cells


Publication metadata

Author(s): Lu X, Ding Z-C, Cao Y, Habtetsion T, Yu M, Lemos H, Mellor AL, Zhou G

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2015

Volume: 194

Issue: 4

Pages: 2011-2021

Print publication date: 15/02/2015

Online publication date: 05/01/2015

Acceptance date: 05/12/2014

ISSN (print): 0022-1759

ISSN (electronic): 1872-7905

Publisher: Elsevier

URL: http://dx.doi.org/10.4049/jimmunol.1401894

DOI: 10.4049/jimmunol.1401894

PubMed id: 25560408


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