DDDR-01. TUMOR ASSOCIATED MACROPHAGES VIS-À-VIS TMZ RESISTANCE IN PTEN-DEFICIENT GLIOMA

Abstract Drug resistance is one of the most important obstacles during chemotherapy. Currently temozolomide (TMZ) is still first line chemotherapy agent for gliomas, while drug resistance is one of the main reasons for chemotherapy failure. It has been reported that tumor-associated macrophages (TAMs) could be related to drug resistance, and thus we have investigated the association between TAMs and TMZ response in gliomas. Firstly, our study have found that PTEN-deficient glioma can specifically induce a large number of M2 phenotype TAMs, which can attenuate the TMZ-mediated the killing effect on glioma cells. Further search for the possible mechanism, we have found TAMs may secrete cytokine IL-6 in PTEN-deficient gliomas, which in turn mediate TMZ resistance. We also revealed that IL-6 highly secreted by TAMs can enhance the stemness of glioma cells through activation of the JAK-STAT3 signaling pathway in PTEN-deficient glioma cells. Secondly, have found valproic acid (VPA) can promote the transformation of TAMs from M2 to M1, reduce its IL-6 secretion, and in turn enhancing sensitivity of TMZ in PTEN-deficient gliomas. Our study revealed that TMZ resistance may modulated through soluble factors released by TAMs. Conventional anti-epilepsy drug- VPA may enhance TMZ sensitivity in PTEN-deficient gliomas, and worth to further clinical investigation. Keywords: PTEN-deficient gliomas; tumor-associated macrophages; valproic acid; temozolomide resistance