Abstract 75P
Background
We have previously shown that a large gene set can classify the tumor immune microenvironment (TIME) of patients with epithelial tumors into one of three phenotypes: immune inflamed (immune hot), immuno-suppressive (immune cold), or immune inert (immune cold). Given that the tumor is constantly evolving, identifying key genes where changes in mutation or cell signaling is associated with a change in phenotypes can lead to identification of potential new targets. Here we show three bioinformatic methodologies for this purpose.
Methods
The first approach to identifies genes hypermethylated in one phenotype and hypomethylated in another as methylation patterns can be surrogates for mutations that drive a transition across the TIME. Second, MUTECT2 annotation was used to detect high impact mutations which were associated with the phenotypes. Third, the IntAct database was used to identify potential cell signaling pairings where one gene was associated with patients classified as hot and a second gene classified patients as cold. All three of these approaches yielded genes with known targeted therapies in active clinical trials.
Results
The methylation approach identified VEGFR2 as a gene where mutations could likely affect TIME phenotypes. VEGFR2 is routinely used in clinical trials and has an approved drug on the market (ramucirumab), and mutations in VEGFR2 are seen to affect patient prognosis and drug sensitivity. With the MUTECT2 approach, mutations in STK11 were identified. Several clinical trials are examining the role that mutations in STK11 can play in altering the treatment paradigm between immunotherapy and KRAS targeted therapy. Finally, the IntAct approach identified the interaction between CRCX4 and CXCL12, known to be involved in TIME evolution and with several clinical trials being conducted designed to disrupt this interaction.
Conclusions
Utilizing a curated gene list to classify patients into TIME phenotypes and then using bioinformatic methods to find genes which may be driving transition across immune of phenotypes resulted in identifying known and well validated targets from current clinical trials. The results argue for a more careful examination of other genes that resulted from this methodology as potential targets for immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Oncocyte.
Disclosure
R. Seitz: Financial Interests, Personal, Advisory Role: Oncocyte, Inc. B. Ring, C. Cronister: Financial Interests, Personal, Full or part-time Employment: Oncocyte, Inc.
Resources from the same session
13P - Universal prospects of cryopreserved umbilical cord blood CD34+ progenitor cell-derived NK cells: Clinical and preclinical evaluation of non-engineered and genetically engineered candidates
Presenter: Anna-Maria Georgoudaki
Session: Cocktail & Poster Display session
Resources:
Abstract
14P - Lentivirally overexpressed c-Myc promoter binding protein (MBP-1) localizes in the cytoplasm of human cutaneous melanoma cell lines increasing cell proliferation and glycolysis rate
Presenter: Miriam Hippner-Kunicka
Session: Cocktail & Poster Display session
Resources:
Abstract
15P - Enhancement Platform for immune Cells (EPiC): invIOs’s innovative cell-therapy platform for creating personalized cancer treatments
Presenter: Mario Kuttke
Session: Cocktail & Poster Display session
Resources:
Abstract
16P - Melatonin modulates energy metabolism and kinases signaling in ovarian cancer cells
Presenter: Luiz Gustavo Chuffa
Session: Cocktail & Poster Display session
Resources:
Abstract
17P - New therapeutic target in triple-negative breast cancer for enhancing PARP inhibitor efficacy and stimulating the anti-tumour immune response
Presenter: Marina Rodriguez-Candela Mateos
Session: Cocktail & Poster Display session
Resources:
Abstract
18P - PARP1 trapping and hyperactivation by the decoy agonist OX425 induces DNA repair abrogation and a robust anti-tumor immune response
Presenter: Vlada Zakharova
Session: Cocktail & Poster Display session
Resources:
Abstract
20P - Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting
Presenter: Pranshu Sahgal
Session: Cocktail & Poster Display session
Resources:
Abstract
21P - Cross-resistance between platinum-based chemotherapy (PlCh) and PARP inhibitors (PARPi) in castration-resistant prostate cancer (CRPC)
Presenter: Peter Slootbeek
Session: Cocktail & Poster Display session
Resources:
Abstract
22P - Emerging role of histone acetyltransferase CBP in breast cancer cells undergoing DNA damage
Presenter: Wafaa Ramadan
Session: Cocktail & Poster Display session
Resources:
Abstract
23P - Synthetic lethality by targeting RHEB in ARID1A-mutated luminal breast cancer
Presenter: Deniz Gulfem Ozturk
Session: Cocktail & Poster Display session
Resources:
Abstract