HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer.
Erasmia T XanthopoulouChristos KakouratosChristos NanosAnastasia G GkegkaChristos KalaitzisAlexandra GiatromanolakiMichael I KoukourakisPublished in: Medical oncology (Northwood, London, England) (2023)
PD-L1/PD-1 pathway is a major pathway exploited by human cancer types, which is a target for current immunotherapy. We investigated tumor microenvironmental factors involved in PD-L1 induction in prostate cancer (PC). We studied the expression of PD-L1 in a series of 66 PCs, in parallel with the expression of hypoxia- and acidity-related immunohistochemical markers (Hypoxia-inducible factor HIF1α, and lactate dehydrogenase LDHA) and tumor-infiltrating lymphocyte TIL density. Experiments with three PC cell lines, the 22Rv1, DU145, and PC3 were conducted focusing on the inducibility of PD-L1 by hypoxia, acidity, lymphocyte interactions, and radiation. In tissues, PD-L1 expression by cancer cells was directly related to PD-L1 expression by TILs and macrophages (p < 0.05), and the overexpression of HIF1α and LDH5 (p < 0.05). TIL density was inversely related to ΗΙF1α (p = 0.02). Exposure of PC cell lines to hypoxia strongly induced PD-L1 and protein and mRNA levels, directly controlled by HIF1α function (p < 0.001). Irradiation with 20 Gy had no apparent effect on PD-L1 expression. Culturing PC cell lines with culture medium (CM) from PBMCs strongly induced PD-L1 at protein and mRNA levels, independently from HIF1α, which was also confirmed when cells were incubated with Interferon-γ (p < 0.001). It is concluded that the combination of anti-PD-L1/PD-1 immunotherapy with hypoxia/HIF-targeting may be important in the treatment of specific subgroups of PC patients.
Keyphrases
- endothelial cells
- high glucose
- prostate cancer
- binding protein
- poor prognosis
- diabetic rats
- radical prostatectomy
- end stage renal disease
- induced apoptosis
- mycobacterium tuberculosis
- gene expression
- drug induced
- peritoneal dialysis
- long non coding rna
- cell proliferation
- squamous cell carcinoma
- newly diagnosed
- papillary thyroid
- amino acid
- dendritic cells
- oxidative stress
- ejection fraction
- chronic kidney disease
- endoplasmic reticulum stress
- protein protein
- prognostic factors
- cell death
- mass spectrometry
- atomic force microscopy
- combination therapy
- lymph node metastasis
- diffusion weighted imaging
- smoking cessation
- high resolution