Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype

Zhi Chun Ding, Bruce R. Blazar, Andrew L. Mellor, David H. Munn, Gang Zhou

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

The functional development of tumor-specific CD4+ T cells has a critical impact on the outcome of antitumor immune responses. Adoptive immunotherapy involving tumor-specific CD4+ T cells has shown encouraging clinical benefits in some cancer patients. To mount an effective antitumor immunity, it is desirable to elicit activated type 1 T helper cells. Here, we report that type 1 T helper cell-like effector cells that arose in tumor-bearing hosts progressively expressed programmed death 1 during tumor growth. The programmed death 1hi effector cells displayed a dysfunctional phenotype, characterized by selective down-regulation of interleukin-7 receptor, heightened apoptosis, and poor antitumor efficacy. This tumor-driven aberrant T-cell response could be prevented by a single dose of the widely used chemotherapy agent cyclophosphamide. We show that chemotherapy conditioned the host environment, creating a transient window for optimal effector differentiation for adoptively transferred CD4+ T cells. This robust effector differentiation, which was antigen-driven and mechanistically dependent on an intact host response to type I interferon, gave rise to activated polyfunctional T helper cells with high interleukin-7 receptor, rapid clonal expansion, and potent antitumor activity against established B-cell lymphomas. We hypothesize that prevention of tumor-induced effector cell dysfunction is a major mechanism contributing to the efficacy of combined chemoimmunotherapy.

Original languageEnglish (US)
Pages (from-to)2397-2406
Number of pages10
JournalBlood
Volume115
Issue number12
DOIs
StatePublished - Mar 25 2010

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Chemotherapy
T-cells
Tumors
Cell Differentiation
T-Lymphocytes
Phenotype
Drug Therapy
Interleukin-7 Receptors
Neoplasms
Th1 Cells
Bearings (structural)
Interferon Type I
Adoptive Immunotherapy
Cyclophosphamide
B-Cell Lymphoma
Helper-Inducer T-Lymphocytes
Cells
Immunity
Apoptosis
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype. / Ding, Zhi Chun; Blazar, Bruce R.; Mellor, Andrew L.; Munn, David H.; Zhou, Gang.

In: Blood, Vol. 115, No. 12, 25.03.2010, p. 2397-2406.

Research output: Contribution to journalArticle

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