Contrasting effects of cyclophosphamide on anti-CTL-associated protein 4 blockade therapy in two mouse tumor models

Yuichi Iida, Nanae Harashima, Takanobu Motoshima, Yoshihiro Komohara, Masatoshi Eto, Mamoru Harada

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Abstract

Immune checkpoint blockade is a promising anticancer therapy, but must be used in combination with other anticancer therapies to increase its therapeutic efficacy. Cyclophosphamide (CP) is a chemotherapeutic drug that shows immune-modulating effects. In this study, we examined the effect of CP on anti-CTL-associated protein 4 (CTLA-4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after i.p. injection of CP (100 mg/kg) followed by anti-CTLA-4 antibody. However, administration in the reverse order increased apoptosis in tumor-specific CD8+ T cells. In the RENCA renal carcinoma model, the antitumor effect of combination therapy was marginal and the tumor-bearing state reduced body weight with an increased serum level of interleukin-6. Interestingly, although CP monotherapy increased myeloid-derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti-CTLA-4 therapy increased MDSCs only in RENCA-bearing mice. Additionally, the serum levels of chemokine ligand 2 and C-X-C motif chemokine 10 were increased by the combination therapy only in RENCA-bearing mice and in vivo depletion of Gr-1+ cells augmented the antitumor effect to some degree. These results reveal a contrasting effect of CP on anti-CTLA-4 therapy between the two mouse tumor models. Cyclophosphamide augments the antitumor effect of anti-CTLA-4 therapy in CT26-bearing hosts, whereas CP after anti-CTLA-4 therapy attenuates this effect through induction of apoptosis in tumor-reactive T cells. Alternatively, CP-induced MDSCs can be increased by anti-CTLA-4 therapy only in RENCA-bearing hosts with an elevated level of interleukin-6.

Original languageEnglish
Pages (from-to)1974-1984
Number of pages11
JournalCancer Science
Volume108
Issue number10
DOIs
Publication statusPublished - Oct 1 2017

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Cyclophosphamide
Neoplasms
Proteins
Therapeutics
Interleukin-6
Chemokine CXCL10
Chemokine CXCL2
Apoptosis
Carcinoma
T-Lymphocytes
Serum
Colon
Spleen
Body Weight
Kidney
Injections
Antibodies

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Contrasting effects of cyclophosphamide on anti-CTL-associated protein 4 blockade therapy in two mouse tumor models. / Iida, Yuichi; Harashima, Nanae; Motoshima, Takanobu; Komohara, Yoshihiro; Eto, Masatoshi; Harada, Mamoru.

In: Cancer Science, Vol. 108, No. 10, 01.10.2017, p. 1974-1984.

Research output: Contribution to journalArticle

Iida, Yuichi ; Harashima, Nanae ; Motoshima, Takanobu ; Komohara, Yoshihiro ; Eto, Masatoshi ; Harada, Mamoru. / Contrasting effects of cyclophosphamide on anti-CTL-associated protein 4 blockade therapy in two mouse tumor models. In: Cancer Science. 2017 ; Vol. 108, No. 10. pp. 1974-1984.
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