Biomarkers of success of anti-PD-(L)1 immunotherapy for non-small cell lung cancer derived from RNA- and whole-exome sequencing: results of a prospective observational study on a cohort of 85 patients.

Autor:	Poddubskaya E; Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.; Vitamed Clinic, Moscow, Russia., Suntsova M; Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.; Laboratory of Translational Genomic Bioinformatic, Moscow Institute of Physics and Technology, Dolgoprudny, Russia., Lyadova M; Oncology Center No. 1, Moscow City Hospital Named after S. S. Yudin, Moscow Healthcare Department, Moscow, Russia., Luppov D; Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.; Laboratory of Translational Genomic Bioinformatic, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.; Department of Molecular Genetic Research, Endocrinology Research Center, Moscow, Russia., Guryanova A; Laboratory of Translational Genomic Bioinformatic, Moscow Institute of Physics and Technology, Dolgoprudny, Russia., Lyadov V; Oncology Center No. 1, Moscow City Hospital Named after S. S. Yudin, Moscow Healthcare Department, Moscow, Russia.; Branch Campus of the Federal State Budgetary Educational Institution of Further Professional Education «Russian Medical Academy of Continuous Professional Education» of the Ministry of Healthcare of the Russian Federation, Novokuznetsk, Russia, Novokuznetsk, Russia., Garazha A; Department of Research, Oncobox Ltd., Moscow, Russia., Sorokin M; Department of Molecular Genetic Research, Endocrinology Research Center, Moscow, Russia.; Department of Research, Oncobox Ltd., Moscow, Russia.; Laboratory for Genomic Analysis of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia., Semenova A; Oncology Center No. 1, Moscow City Hospital Named after S. S. Yudin, Moscow Healthcare Department, Moscow, Russia., Shatalov V; Oncology Center No. 1, Moscow City Hospital Named after S. S. Yudin, Moscow Healthcare Department, Moscow, Russia., Biakhova M; Oncology Center No. 1, Moscow City Hospital Named after S. S. Yudin, Moscow Healthcare Department, Moscow, Russia., Simonov A; Laboratory of Translational Genomic Bioinformatic, Moscow Institute of Physics and Technology, Dolgoprudny, Russia., Moisseev A; Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.; Department of Molecular Genetic Research, Endocrinology Research Center, Moscow, Russia., Buzdin A; Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.; Laboratory of Translational Genomic Bioinformatic, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.; Laboratory for Genomic Analysis of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.; PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Dec 12; Vol. 15, pp. 1493877. Date of Electronic Publication: 2024 Dec 12 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1493877
Abstrakt:	Background: Immune checkpoint inhibitors (ICIs) treatment have shown high efficacy for about 15 cancer types. However, this therapy is only effective in 20-30% of cancer patients. Thus, the precise biomarkers of ICI response are an urgent need. Methods: We conducted a prospective observational study of the prognostic potential ofseveral existing and putative biomarkers of response to immunotherapy in acohort of 85 patients with lung cancer (LC) receiving PD-1 or PD-L1 targeted ICIs. Tumor biosamples were obtained prior to ICI treatment and profiled by whole exome and RNA sequencing. The entire 403 putative biomarkers were screened, including tumor mutation burden (TMB) and number of cancer neoantigens, 131 specific HLA alleles, homozygous state of 11 HLA alleles and their superfamilies; four gene mutation biomarkers, expression of 45 immune checkpoint genes and closely related genes, and three previously published diagnostic gene signatures; for the first time, activation levels of 188 molecular pathways containing immune checkpoint genes and activation levels of 19 pathways algorithmically generated using a human interactome model centered around immune checkpoint genes. Treatment outcomes and/or progression-free survival (PFS) times were available for 61 of 85 patients with LC, including 24 patients with adenocarcinoma and 27 patients with squamous cell LC, whose samples were further analyzed. For the rest 24 patients, both treatment outcomes and PFS data could not be collected. Of these, 54 patients were treated with PD1-specific and 7 patients with PD-L1-specific ICIs. We evaluated the potential of biomarkers based on PFS and RECIST treatment response data. Results: In our sample, 45 biomarkers were statistically significantly associated with PFS and 44 with response to treatment, of which eight were shared. Five of these (CD3G and NCAM1 gene expression levels, and levels of activation of Adrenergic signaling in cardiomyocytes, Growth hormone signaling, and Endothelin molecular pathways) were used in our signature that showed an AUC of 0.73 and HR of 0.27 (p=0.00034) on the experimental dataset. This signature was also reliable (AUC 0.76, 0.87) for the independent publicly available LC datasets GSE207422, GSE126044 annotated with ICI response data and demonstrated same survival trends on independent dataset GSE135222 annotated with PFS data. In both experimental and one independent datasets annotated with samples' histotypes, the signature worked better for lung adenocarcinoma than for squamous cell LC. Conclusion: The high reliability of our signature to predict response and PFS after ICI treatment was demonstrated using experimental and 3 independent datasets. Additionally, annotated molecular profiles obtained in this study were made publicly accessible. Competing Interests: Authors AG and MS were employed by the company Oncobox Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Poddubskaya, Suntsova, Lyadova, Luppov, Guryanova, Lyadov, Garazha, Sorokin, Semenova, Shatalov, Biakhova, Simonov, Moisseev and Buzdin.)
Databáze:	MEDLINE
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