Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells

Xiaoyun Lu, Zhi Chun Ding, Yang Cao, Chufeng Liu, Tsadik Habtetsion, Miao Yu, Henrique Lemos, Huda Salman, Hongyan Xu, Andrew L. Mellor, Gang Zhou

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2011-2021
Number of pages11
JournalJournal of Immunology
Volume194
Issue number4
DOIs
StatePublished - Feb 15 2015

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Adoptive Immunotherapy
Melphalan
Alkylating Agents
T-Lymphocytes
Neoplasms
Cell- and Tissue-Based Therapy
Calreticulin
Therapeutics
B-Cell Lymphoma
Therapeutic Uses
Multiple Myeloma
Chemokines
Endoplasmic Reticulum
Immunotherapy
Dendritic Cells
Colorectal Neoplasms
Cell Death
Lymph Nodes
Cytokines
Drug Therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. / Lu, Xiaoyun; Ding, Zhi Chun; Cao, Yang; Liu, Chufeng; Habtetsion, Tsadik; Yu, Miao; Lemos, Henrique; Salman, Huda; Xu, Hongyan; Mellor, Andrew L.; Zhou, Gang.

In: Journal of Immunology, Vol. 194, No. 4, 15.02.2015, p. 2011-2021.

Research output: Contribution to journalArticle

Lu, Xiaoyun ; Ding, Zhi Chun ; Cao, Yang ; Liu, Chufeng ; Habtetsion, Tsadik ; Yu, Miao ; Lemos, Henrique ; Salman, Huda ; Xu, Hongyan ; Mellor, Andrew L. ; Zhou, Gang. / Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. In: Journal of Immunology. 2015 ; Vol. 194, No. 4. pp. 2011-2021.
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