Neoadjuvant Chemotherapy Induces IL34 Signaling and Promotes Chemoresistance via Tumor-Associated Macrophage Polarization in Esophageal Squamous Cell Carcinoma
The tumor microenvironment (TME) plays a critical role in determining the effectiveness of neoadjuvant chemotherapy (NAC) in solid tumors, including esophageal squamous cell carcinoma (ESCC). However, the specific TME characteristics of ESCC treated with NAC remain incompletely understood. In this study, we explored how NAC influences the TME, particularly focusing on tumor-associated macrophages (TAMs), which are key immunosuppressive elements of the TME in ESCC. We measured the expression of CD163, a key marker for TAMs, in both pre-therapy biopsies and surgically resected ESCC specimens from patients ARRY-382 who received NAC (n = 33) or did not receive NAC (n = 12). Our findings revealed that NAC significantly elevated CD163 expression in TAMs within ESCC tumors.
Colony-stimulating factor 1 (CSF-1) and IL34 are critical cytokines responsible for recruiting monocytes to tumor sites and facilitating their differentiation into TAMs. Notably, NAC significantly increased the expression of IL34, but not CSF-1, in tumor cells, and we observed a strong correlation between CD163+ TAM frequency and IL34 expression in post-NAC ESCC. IL34 expression was markedly higher in NAC-nonresponsive patients compared to NAC-responsive patients, and patients with IL34-high ESCC had a poorer prognosis compared to those with IL34-low ESCC. Additionally, we demonstrated that 5-fluorouracil (5-FU)/cisplatin selectively upregulated IL34 mRNA expression in human ESCC cell lines. When human peripheral blood monocytes were co-cultured with ESCC cells treated with 5-FU/cisplatin, CD163 expression increased, but this effect was reduced when CSF-1R inhibitors were used.
These results suggest that NAC induces IL34 expression, shifting the TME toward an immunosuppressive, CD163+ TAM-rich environment that is resistant to chemotherapy in ESCC. **IMPLICATIONS:** Targeting IL34 signaling could represent a novel therapeutic approach to combat chemoresistance in ESCC by preventing the polarization of TAMs into the immunosuppressive M2 phenotype.