Analysis of HSP27 and the autophagy marker LC3B+ puncta following preoperative chemotherapy identifies high-risk osteosarcoma patients

Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression. The staining percentage and intensity for each marker were scored and the extent to which marker expression was correlated with pathologic response, relapse-free survival (RFS), and overall survival (OS) was assessed. LCB3+ puncta in post-treatment primary tumors (50%) and metastases (67%) was significantly higher than in pre-treatment biopsy specimens (30%; p=0.023 and <0.001). Among 215 patients with localized osteosarcoma, both pre-treatment (multivariate hazard ratio [HR]=26.7 [95% confidence interval=1.47-484], p=0.026) and post-treatment HSP27 expression (multivariate HR=1.85 [1.03-3.33], p=0.039) were associated with worse OS. Lack of LC3B+ puncta at resection was an independent poor prognostic marker in both univariate (HR=1.78 [1.05-3.03], p=0.034) and multivariate models (HR=1.75 [1.01-3.04], p=0.045). Patients with LC3B+/HSP27- tumors at resection had the best 10-year OS (75%) whereas patients with LC3B-/HSP27+ tumors had the worst 10-year survival (25%). Neither HSP27 expression nor the presence of LCB3+ puncta was correlated with pathologic treatment response. Our findings establish HSP27 expression and LC3B+ puncta as independent prognostic markers in osteosarcoma patients receiving standard chemotherapy and support further investigation into strategies targeting HSP27 or modulating autophagy in osteosarcoma treatment.

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