Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells

Toshiki Iwai, Yui Harada, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Yoshikazu Yonemitsu

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Abstract

The anti-VEGF humanized antibody bevacizumab suppresses various malignancies, but tumors can acquire drug resistance. Preclinical studies suggest myeloid-derived suppressor cells (MDSCs) may be associated with tumor refractoriness to anti-VEGF treatment. Here we report a novel mechanism of tumor escape from anti-VEGF therapy. Anti-VEGF treatment enhanced intratumoral recruitment of CD11bhigh/Gr- 1high polymorphonuclear (PMN)-MDSCs in anti-VEGF-resistant Lewis lung carcinoma tumors. This effect was diminished by the anticancer agent capecitabine, a prodrug converted to 5-fluorouracil, but not by 5-fluorouracil itself. This process was mediated by enhanced intratumoral granulocyte-colony stimulating factor expression, as previously demonstrated. However, neither interleukin-17 nor Bv8, which were previously identified as key contributors to anti-VEGF resistance, was involved in this model. Capecitabine eliminated PyNPase-expressing MDSCs from both tumors and peripheral blood. Capecitabine treatment also reversed inhibition of both antitumor angiogenesis and tumor growth under anti-VEGF antibody treatment, and this effect partially inhibited in tumors implanted in mice deficient in both PyNPases. These results indicate that intratumoral granulocyte-colony stimulating factor expression and CD11bhigh/Gr-1high PMN-MDSC recruitment underlie tumor resistance to anti-VEGF therapy, and suggest PyNPases are potentially useful targets during anti-angiogenic therapy.

Original languageEnglish
Pages (from-to)17620-17630
Number of pages11
JournalOncotarget
Volume9
Issue number25
DOIs
Publication statusPublished - Apr 1 2018

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Tumor Escape
Myeloid Cells
Vascular Endothelial Growth Factor A
Neoplasms
Granulocyte Colony-Stimulating Factor
Fluorouracil
Lewis Lung Carcinoma
Antibodies, Monoclonal, Humanized
Interleukin-17
Capecitabine
Prodrugs
Drug Resistance
Antineoplastic Agents
Anti-Idiotypic Antibodies
Therapeutics
Myeloid-Derived Suppressor Cells

All Science Journal Classification (ASJC) codes

  • Oncology

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Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells. / Iwai, Toshiki; Harada, Yui; Saeki, Hiroshi; Oki, Eiji; Maehara, Yoshihiko; Yonemitsu, Yoshikazu.

In: Oncotarget, Vol. 9, No. 25, 01.04.2018, p. 17620-17630.

Research output: Contribution to journalArticle

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