TY - JOUR
T1 - Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells
AU - Iwai, Toshiki
AU - Harada, Yui
AU - Saeki, Hiroshi
AU - Oki, Eiji
AU - Maehara, Yoshihiko
AU - Yonemitsu, Yoshikazu
N1 - Funding Information:
This study was supported in part by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (15638738 and 16690166 to Y.M., and 16690165 to Y.Y.), and in part by Chugai Pharmaceutical Co. Ltd. We thank Mitsue Kurasawa, Keigo Yorozu (Product Research Department, Chugai Pharmaceutical) and Hiroshi Fujii (Department of Pathology, Kyushu University) for help with the immunohistochemistry, and Kaname Yamamoto, Naoki Harada, Kaori Fujimoto-Ouchi and Kazushige Mori (Product Research Department, Chugai Pharmaceutical) for the helpful discussion and comments.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
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U2 - 10.18632/oncotarget.24811
DO - 10.18632/oncotarget.24811
M3 - Article
AN - SCOPUS:85044838975
VL - 9
SP - 17620
EP - 17630
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 25
ER -