6533b7d3fe1ef96bd126016a

RESEARCH PRODUCT

In the literature: August 2020.

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Immune checkpoint inhibitors (ICI) have become a key component of therapy for several solid tumours. In patients diagnosed with advanced clear cell renal cell carcinoma (ccRCC), immunotherapy has always been considered as a treatment option, and anti-PD-1-based therapies are approved in both the frontline and refractory settings. Response to PD-1 blockade has been associated with numerous tumour-intrinsic and microenvironment features. Genetic characterisation of ccRCC has significantly contributed to the knowledge of tumour biology and the mechanisms of disease progression, but the interplay of genomic alterations with patterns of immune infiltration in response to PD-1 blockade remains undefined.1 It is also well known that ccRCC has only a modest mutational burden and a high infiltration of CD8+ T cells. Recently, a very interesting article has been published in Nature Medicine by Braun et al ,2 trying to answer several questions regarding the relation of molecular alterations and response to ICI in ccRCC. The authors performed an integrated genomic, transcriptomic and immunopathologic analysis of advanced-stage ccRCC tumours derived from 592 patients enrolled in three prospective clinical trials of PD-1 blockade to evaluate the landscape of somatic alterations, copy number changes, the patterns of immune infiltration and the clinical outcome to PD-1 blockade. In this cohort, an integrated genomic and transcriptomic analysis with immune phenotyping by CD8 immunofluorescence was performed showing that CD8+ T-cell infiltrated tumours are relatively depleted for PBRM1 mutations, which is associated with response to CPI, while are enriched for chromosomal losses of 9p21.3 associated with resistance to PD-1 blockade in infiltrated tumours. Overall, although infiltrated tumours are considered immunogenically ‘hot’, they are relatively depleted of PBRM1 mutations,3 which correlate with improved survival with anti-PD-1 therapy and are enriched for 9p21.3 deletions, which are associated with worse outcomes after PD-1 blockade. This integrative approach provides a potential …