The loss of the of the tumor suppressor gene VHL and the subsequent deregulation of VHL/HIF/VEGF signalling are known to play a role in development of clear cell renal cell carcinoma (ccRCC). Renal tumours associated with BHD syndrome are histologically diverse and include a percentage of ccRCC (Pavlovich et al., 2002). Anti-angiogenic therapies targeting the VHL/HIF/VEGF pathway have emerged in past years (Rini et al., 2006) but the development of resistance to these therapeutic agents is leading to the development of a new approach based on targeted immunotherapy against immune checkpoint PD1/PDL1 to restore antitumor immune response. In a new study Kammerer-Jacquet et al. (2016) assessed a large series of 98 cases of ccRCC and correlated PDL1 expression with clinical data follow-up of up to 10 years, expression of VEGF, PAR-3, CAIX and PD-1 and complete VHL status. The authors found PD-L1 expression to be associated with non-inactivated VHL tumors and in particular wild-type VHL ccRCC. These tumors could benefit from therapies inhibiting PD-L1/PD-1.
The authors summarized the 98 patient population characteristics and pathological parameters. Tumors with two alterations of the VHL gene (66.3%) were classed as inactivated (inVHL). Those with one or no alteration (33.7%) were grouped as non-inactivated VHL tumors (niVHL). Within this group, tumors with no alteration (11.2%) were classed as wild-type (wtVHL). PD-L1 expression by immunohistochemistry (IHC) was observed in 70.4% of tumors with different patterns of expression. Tumors with PD-L1 expression were associated with a higher tumor stage and metastasis at diagnosis, higher ISUP grade, sarcomatoid component, overexpression of VEGF and PAR-3 protein and dense TIL PD-1 expression. PD-L1 expression was associated with niVHL ccRCC and, in particular, all wtVHL subgroup tumors expressed PD-L1. Expression of PD-1 and the niVHL gene was significantly associated with PD-L1 expression in a multivariate analysis. Patients with PD-L1 expression had a worse prognosis than patients with no PD-L1 with a lower median specific survival from nephrectomy.
In some cancer cases, it has been shown that PD-L1 expression is driven by oncogenic signalling pathways such as PI3K-AKT and MAPK pathways and is termed innate immune resistance (Atefi et al., 2014; Chen et al., 2016). Alternatively, PD-L1 expression in tumors may be induced via adaptive tumor-specific immune signals (Spranger et al., 2014). PD-L1 expression in ccRCC have been previously associated with metastasis, poor outcome and poor prognostic factors such as VEGF expression (Thompson et al., 2007; Shin et al., 2016). Another study reported PD-L1 expression and fewer VHL gene mutations in ccRCC4 tumors. This subtype of metastatic primary ccRCC was associated with poor prognosis under anti-angiogenic therapy with sunitinib, a targeted tyrosine kinase inhibitor (TKI) (Beuselinck et al. 2015). In the present study, wtVHL ccRCC were particularly associated with PD-L1 expression supporting the mechanism of overexpression of PD-L1 being associated with alternative oncogenic pathways in ccRCC despite HIF degradation due to the presence of an activated VHL protein (niVHL). niVHL tumors could use alternative pathways independent of VHL mechanisms such as the MAPK and PI3K-AKT-mTOR pathways involved in ccRCC oncogenesis (Robb et al., 2007; Huang et al., 2008; Mendoza et al., 2011).
In summary, and for the first time, PD-L1 expression by IHC was found to be associated with niVHL tumors, and in particular with wtVHL ccRCC. These tumors may benefit from immunotherapy inhibiting PDL1/PD-1 to produce long-lasting responses in patients. Other advances in immunotherapy for renal cell carcinoma have been discussed in a previous blog.
- Kammerer-Jacquet SF, Crouzet L, Brunot A, Dagher J, Pladys A, Edeline J, Laguerre B, Peyronnet B, Mathieu R, Verhoest G, Patard JJ, Lespagnol A, Mosser J, Denis M, Messai Y, Gad-Lapiteau S, Chouaib S, Belaud-Rotureau MA, Bensalah K, & Rioux-Leclercq N (2016). Independent association of PD-L1 expression with non-inactivated VHL clear cell renal cell carcinoma – a finding with therapeutic potential. International journal of cancer PMID: 27623354