Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues
- 31 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 70 (6), 1755-1769
- https://doi.org/10.1007/s00262-020-02799-y
Abstract
Background Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR. Methods Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples. Results The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8(+) tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8(+) T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-gamma pathway were detected in any patient. Conclusions Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.Funding Information
- Korea Health Industry Development Institute (HI17C2085)
- Seoul National University Hospital Research Fund (03-2015-0380)
This publication has 54 references indexed in Scilit:
- Signatures of mutational processes in human cancerNature, 2013
- An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancersNature Genetics, 2013
- Deciphering Signatures of Mutational Processes Operative in Human CancerCell Reports, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Mutational Processes Molding the Genomes of 21 Breast CancersCell, 2012
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal of Cancer, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- KEGG: Kyoto Encyclopedia of Genes and GenomesNucleic Acids Research, 2000