FIRMST abstract 2020.51

FIRMST2020-AB51
IMMUNE EVASION OFFERS NOVEL INSIGHTS INTO THE EVOLUTIONARY TRAJECTORY OF UROLOGY’S MOST DEADLY CANCER

Faiz JABBAR1
University College London, United Kingdom

Aim: 
We investigated whether genomic alterations causing allelic imbalance to human leukocyte antigen (AIHLA) alleles would facilitate immune evasion, subsequently promoting proliferation and metastasis.


Keywords: Latanoprost, Bimatoprost, Primary Open Angle Glaucoma (POAG), Water Drinking Test (WDT), Intra ocular pressure (IOP).




correspondence 
zchafja@ucl.ac.uk
conflict of interest none

Article Information
Epub: 20.09.2020
Presented at FIRMST Conference, Moscow 2020
Peer reviewed by JS Bamrah, Ananthakrishnan Raghuraman, Soumit Dasgupta
Open Access- Creative Commons Licence CC-BY-ND-4.0

Background: 
Renal cell carcinoma (RCC) is the deadliest urological malignancy. Although the treatment of primary RCC has become more successful, five-year survival rates for metastatic RCC remains low at 8%. Large-scale studies of metastatic disease have not analysed paired primary-metastatic tumours, a requirement to distinguish between tumours with and without metastatic potential. An improved understanding of the genetic differences between primary and metastatic tumours could reveal exploitable vulnerabilities that may prevent metastasis and/or improve prognosis.
 
Method
We acquired the ability to decipher potential modes of metastatic progression through simultaneous analysis of 418 primary and 278 metastatic biopsies from 31 renal cell carcinoma patients. Multiple regions from each tumour were biopsied giving us clonal resolution. AI was investigated using fluorescently labelled STR oligonucleotides that were polymorphic within the HLA locus. 

Results: 
I categorised them into three groups based on evidence of selection in the metastasis. “Selected” frequencies were compared to “not selected”. Significance was calculated by comparing event selection proportions, to null background mutation rates. 

AIHLA was significantly associated with metastasis, suggesting AIHLA contributes to metastasis (p=0.002). Immunohistochemical analysis on 897 tumour biopsies stained for the proliferation marker Ki67 showed increased proliferative potential in AIHLA-positive versus AIHLA-negative biopsies.

Discussion: 
These results suggest escape from immune predation represents a significant constraint to tumour evolution and AIHLA could facilitate evasion, thereby contributing to metastasis. An investigation of the HLA alleles lost may help determine which neoantigens will elicit an effective immune response and so could be exploited by personalised immunotherapies.

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