HSP10, HSP60, and HSP70 overexpression associates with PD-L1 upregulation and adverse outcomes in on-small cell lung cancer.

BACKGROUND

HSP10, HSP60, and HSP70, members of the heat shock protein (HSP) family, are cytoprotective stress-response chaperones involved in protein homeostasis and critical pathways, including inflammation. Aberrant expression of these proteins has been observed in many tumors and is associated with patients' prognosis. Immunotherapy with checkpoint inhibitors, particularly those targeting the Programmed Death-1 (PD-1)/ Programmed Death Ligand 1 (PD-L1) axis, has emerged as a highly promising therapeutic approach for non-small cell lung cancer (NSCLC).

METHODS

Public databases and bioinformatics analyses were employed to investigate the relationship between HSP10, HSP60, HSP70 and PD-L1. This predicted association was further validated using immunohistochemistry (IHC) on tissue microarrays (TMAs) comprising 43 cases of adjacent non-cancerous lung tissue (Non-CLT) and 433 cases of surgically resected NSCLC (including 294 cases of adenocarcinoma and 139 cases of squamous cell carcinoma). Additionally, the correlation between the expression of these HSPs and the clinicopathological features of NSCLC was examined.

RESULTS

Pan-cancer analysis revealed significantly elevated levels of HSP10, HSP60 and HSP70 in most cancers compared to normal tissues. In NSCLC, these HSPs showed markedly higher expression at both mRNA and protein levels than in adjacent Non-CLT. Patients with advanced clinical stage or lymph node metastasis (LNM) exhibited higher HSP60 and HSP70 expression than those with early-stage disease or no LNM. Notably, all three HSPs demonstrated positive correlations with both PD-L1 expression (mRNA and protein levels) but negative correlations with the infiltration of most immune cells. Moreover, elevated these three HSPs expression was associated with significantly shorter overall survival (OS) time in NSCLC patients. Multivariate analysis confirmed that overexpression of HSP10, HSP60, and HSP70 was identified as a poor prognostic factor for NSCLC.

CONCLUSIONS

High expression of HSP10, HSP60, and HSP70 correlates with PD-L1 levels may serve as novel biomarkers for poor prognosis in NSCLC patients.