1907P - Multi-omics mapping positions antigenic myeloid-T cell crosstalk at the core of advanced renal cell carcinoma (aRCC) response to immune checkpoint blockade (ICB)

Background

ICB can achieve durable benefit in aRCC, but reliable biomarkers are lacking. Despite ongoing research, current aRCC biomarkers fail across trials.

Methods

We performed a comprehensive biomarker discovery in our in house, real world aRCC transcriptomic dataset of ICB treated patients (anti-CTLA4+anti-PD1 and anti-PD1) with corresponding human leukocyte antigen (HLA) genotypes to characterize antigen presenting features. Using machine learning (ML) as a wrapper, a transcriptomic biomarker set reflecting HLA promiscuity (HLApr) was developed. We studied its impact on outcome in our ICB treated cohort, in external ICB treated aRCC cohorts (IMmotion150/Miao et al/Choueiri et al, Javelin101) and post-nephrectomy patients (TCGA KIRC).

Results

Increased tumor-relevant antigen binding specificity of HLAs over other antigens (low HLApr) correlated with improved overall survival (OS) after ICB (hazard ratio (HR) 0,4; 95% CI 0,21-0,75, p=0,004, n=98), independent of IMDC risk groups on multivariable analysis, and with a trend towards longer progression free survival (PFS) (HR 0,69, 95%CI 0,38-1,27, p=0,2). Analysis of immunopeptidome-derived and experimentally-validated HLA allele-antigen pairs confirmed that HLA alleles with lower HLApr and correlated with OS upon ICB preferentially bound neo-antigens. A ML based signature was developed that cross-linked transcriptomic footprints with low HLApr, which correlated with OS in our ICB treated cohort (HR 0,56, 95%CI 0,34-0,94, p=0,03), and trended towards correlation with PFS (HR 0,66, 95%CI 0,42-1,03, p=0,07). The signature correlated with PFS in external ICB treated cohorts Javelin101 (HR 0,73, 95%CI 0,54-0,99, p=0,04, n=354) and IMmotion150/Miao et al/Choueiri et al (HR 0,47, 95%CI 0,26-0,86, p=0,015, n=207) and with OS in TCGA KIRC (HR 0,52, 95%CI 0,38-0,71, p<0,001, n=511). In Departmenth tumor immune analyses identified antigen presentation, interferon signalling and myeloid-T cell crosstalk as determinants of ICB responders.

Conclusions

In Departmenth multi-omics analysis revealed critical importance of antigenic myeloid-T cell crosstalk, driven by high neo-antigenicity, to ensure adequate ICB response in aRCC.

Clinical trial identification

S53479/S63833.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

“Kom op tegen Kanker” (Stand up to Cancer), Flemish cancer society. Research Foundation Flanders (FWO). Unrestricted research grants of Pfizer and Ipsen. iBOF grant (VLIR UoS). KU Leuven (C1, C3 grants). Company funding from Boehringer Ingelheim, SOTIO and BMS.

Disclosure

All authors have declared no conflicts of interest.