A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.
Objective
To evaluate whether remote ischaemic preconditioning (RIPC) reduces renal injury in patients undergoing laparoscopic partial nephrectomy (LPN).
Patients and methods
In all, 82 patients undergoing LPN were randomly assigned to either the RIPC or control group, with 40 and 38 patients, respectively completing 6‐months follow‐up.
RIPC was conducted after induction of anaesthesia, which consisted of three 5‐min cycles of right lower limb ischaemia and 5 min of reperfusion during each cycle.
The primary outcome was the absolute change in glomerular filtration rate (GFR) of the affected kidney by renal scintigraphy from baseline to 6 months.
The secondary outcomes included urinary retinol‐binding protein (RBP) levels measured at 24 and 48 h, serum creatinine, and estimated GFR (eGFR) at 1 and 6 months, and changes in GFR by renal scintigraphy.
Results
There were no differences in the change of GFR of the affected kidney at 6 months, while it was significantly decreased by 15.0% in the control group vs 8.8% in the RIPC group at 1 month (P = 0.034).
The urinary RBP levels increased 8.4‐fold at 24 h in the control group compared with a lower increase of 3.9‐fold in the RIPC group (P < 0.001).
There were no differences in the serum creatinine level or eGFR at 1 and 6 months between the two groups.
Conclusions
In patients undergoing LPN, RIPC using transient lower limb ischaemia may reduce renal impairment in the short term, but failed in the longer term despite a non‐significant trend in favour of RIPC.
These novel data support the need for a larger study of RIPC during LPN surgery.
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