Abstract 15P
Background
The feasibility of immune checkpoint inhibitors, such as anti-PD-1, remains low because of poor patient selection. We aimed to find predictive biomarkers of resistance to immune checkpoint inhibitors using publicly available transcriptomic and clinical data.
Methods
An online analysis platform (https://rocplot.com/immune) with 1,434 samples from distinct tumor types was set up. Genes overexpressed in non-responding patients were selected based on Mann-Whitney test, receiver operating characteristics (ROC) curve, and survival analysis using KM-plotter immune web platform. A clinically approved, druggable target was selected using a literature search. Cytotoxicity of the selected target was tested in vitro, then used in C57BL/6JRj mice to investigate combinational effects with anti-PD-1 immune checkpoint inhibitor.
Results
Yes-Associated Protein 1 (YAP1) was the best druggable target overexpressed in non-responding patients (ROC AUC=0.7, FC=1.8, PROC=7.5E-11) in the anti-PD-1 melanoma pre-treatment cohort (n=415). Patients with higher YAP1 expression showed worse progression-free survival (HR=2.51, P=1.2E-06, log-rank test) and overall survival (HR=2.15, P=1.2E-05). Verteporfin (VP), a YAP1 inhibitor, was chosen for combination therapy. We found that VP significantly decreased the viability of immunologically 'cold' melanoma cell lines B16-F10 and YUMM1.7 after 48 hours at concentrations of 0.1 μM (P=0.001) and 1 μM (P<0.001), respectively (one-way ANOVA). Compared to anti-PD-1 monotherapy (P=0.008, independent t-test) or IgG2a isotype control (P=0.021) groups, the combination of VP with anti-PD-1 demonstrated greater efficiency in YUMM1.7-inoculated mice. Neither VP nor anti-PD-1 exhibited significant tumor growth inhibition compared to the control (P>0.05, independent t-test). In the anti-PD-1 plus VP therapy group, CD3 (P=0.05), CD45 (P<0.05), CD68 (P=0.01), CD86 (P<0.05), and CD80 (P=0.01) had higher expression compared to control (one-way ANOVA).
Conclusions
A feasible immuno-oncology database was set up for the discovery of predictive biomarkers. A druggable target (YAP1) was chosen for in vitro and in vivo validation. YAP1 inhibitor Verteporfin exhibited higher efficacy in treating melanoma in mice.
Legal entity responsible for the study
The authors.
Funding
National Research, Development and Innovation Office (Hungary): PharmaLab (RRF-2.3.1-21-2022-00015), RRF-2.3.1-21-2022-00003, and 2022-1.1.1-KK-2022-00005. European Union's Horizon 2020 Programme: Grant agreement no. 739593. Hungarian Academy of Sciences: Momentum Research Grant (LP-2021-14). Ministry for Innovation and Technology (Hungary): New National Excellence Program (ÚNKP-23-4-I-SE-5) and KDP-2020 funding scheme (KDP-14-3/PALY-2021).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
7P - ACOX2 disturbs the stability of MRE11-RAD50-NBS1 complex and shapes activated immune tumor microenvironment in clear cell renal cell carcinoma
Presenter: Shiqi Ye
Session: Poster Display session
Resources:
Abstract
9P - CXCR6+PD-1- Tissue Resident memory T cells are associated with poor prognosis in patients with metastatic colorectal cancer
Presenter: Emilien Laloy
Session: Poster Display session
Resources:
Abstract
10P - Tumor-infiltrating lymphocytes and tertiary lymphoid structures in oral cavity squamous cell carcinoma in non-smokers and non-drinkers: Predict clinical outcome
Presenter: Israa Laklouk
Session: Poster Display session
Resources:
Abstract
11P - Tumor-infiltrating lymphocytes on routine H&E staining with automated quantification predict outcomes in resectable non-small cell lung cancer
Presenter: Guus Heuvel
Session: Poster Display session
Resources:
Abstract
12P - Epithelial-mesenchymal transition facilitates response to AXL/PD-1 inhibition in relapsed mesothelioma
Presenter: Essa Baitei
Session: Poster Display session
Resources:
Abstract
14P - Integrated genomic analysis of whole genomes to derive a biomarker of durable response to immunotherapy in melanoma
Presenter: Irene Lobon
Session: Poster Display session
Resources:
Abstract
16P - Immune checkpoint blockade and HLA-related epistasis in melanoma: Genetic determinants of response and toxicity
Presenter: Martin Little
Session: Poster Display session
Resources:
Abstract
17P - Identification PD-L1-associated lncRNA biomarkers for immunoregulation in ovarian cancer
Presenter: Hee Jung Kim
Session: Poster Display session
Resources:
Abstract
19P - Genetic profiling of early triple-negative breast cancer patients with an indication for neoadjuvant pembrolizumab
Presenter: Bogdan Popescu
Session: Poster Display session
Resources:
Abstract
21P - Impact of TP53 mutation subtypes on the efficacy of anti-PD-(L)1 immunotherapy in patients with non-small cell lung cancer
Presenter: Lige Wu
Session: Poster Display session
Resources:
Abstract