Tumor-associated macrophages modulate resistance to oxaliplatin via inducing autophagy in hepatocellular carcinoma

Abstract

BackgroundOxaliplatin-based chemotherapy is widely used to treat hepatocellular carcinoma (HCC). Recent studies suggested that therapeutic resistance of tumors was affected by tumor microenvironment (TME). As a major component of TME, the role of tumor-associated macrophages (TAMs) on drug resistance in HCC is largely unknown.Methods26 HCC samples were obtained from patients who had underwent transarterial chemoembolization (TACE) within 3 months before receiving curative resections. Immunohistochemistry was applied to detect the density of TAMs in these tissues. SMMC-7721 and Huh-7 cell lines were used to co-culture with THP-1 derived macrophages. Under oxaliplatin treatment, cell death was measured using MTT and annexin V/propidium iodide assays. Autophagy activation was evaluated by GFP-LC3 redistribution and LC3 conversion in SMMC-7721 and Huh-7. Short-interfering RNA against ATG5 gene was applied to inhibit autophagy. In vivo validation was conducted in Huh-7 with or without macrophages using an HCC xenograft model in nude mice after oxaliplatin administration.ResultsWe found that the density of TAMs in HCC samples was associated with the efficacy of TACE. Macrophages inhibited cell death induced by oxaliplatin in HCC cells. Autophagy was functionally activated in HCC cells after co-culturing with macrophages. Suppression of autophagy using RNA interference of ATG5 in HCC cells promoted the oxaliplatin cytotoxicity in the co-culture system. Critically, co-implantation with macrophages in HCC xenografts weakens cytotoxic effect of oxaliplatin through inducing autophagy to avoid apoptosis.ConclusionsOur results suggest that TAMs induce autophagy in HCC cells which might contribute to oxaliplatin resistance. Targeting TAMs is a promising therapeutic strategy to enhance the effects of chemotherapy oxaliplatin in HCC patients.

Anti-Proliferative Effects of an Extra-Virgin Olive Oil Extract Enriched in Ligstroside Aglycone and Oleocanthal on Human Liver Cancer Cell Lines

“…As an example, autophagy induced by tumor-associated macrophages protects Huh7 cells against oxaliplatin-dependent cytotoxicity. Such protection is abrogated when autophagy is inhibited by ATG5 silencing [38]. Along this line, the present results suggest that liver cancer cells try to face the challenge imposed by EVOO extract by activating autophagy above control levels (increased LC-3 II/LC-3 I ratio) but are unable to reach complete autophagosome degradation (high p62 levels) and eventually die.…”

Comprehensive Study of Tumor Immune Microenvironment and Relevant Genes in Hepatocellular Carcinoma Identifies Potential Prognostic Significance

“…Different subtypes of liver macrophages exhibit diverse ontogeny, differentiation, and function, especially Kupffer cells and tumor-associated macrophages (TAMs) (42). TAMs play an important role in the occurrence, development, invasion, metastasis, immune evasion, and angiogenesis in HCC (43). Kupffer cells enhance virus-mediated inflammation, causing liver cirrhosis and HCC (44).…”

Dendrimer size effects on the selective brain tumor targeting in orthotopic tumor models upon systemic administration

“…Tumor‐associated macrophages (TAMs) have emerged as promising therapeutic targets for cancer treatment due to their abundance within tumors and their critical roles in manipulating the immune environment toward a pro‐tumor state 13 . Tumors actively recruit host macrophages and monocytes and repolarize them into TAMs, which suppress immune activation and promote tumor growth, metastasis, and drug resistance 14‐16 . Therefore, immunotherapies that can reprogram TAMs from a pro‐tumor to an anti‐tumor phenotype can inhibit their tumor‐supporting functions while simultaneously bolstering their immune activation and antigen‐presenting functions 17,18 .…”