High tumor mutational burden and T-cell activation are associated with long-term response to anti-PD1 therapy in Lynch syndrome recurrent glioblastoma patient
- 3 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 70 (3), 831-842
- https://doi.org/10.1007/s00262-020-02769-4
Abstract
Background Glioblastomas (GBMs) in patients harboring somatic or germinal mutations of mismatch-repair (MMR) genes exhibit a hypermutable phenotype. Here, we describe a GBM patient with increased tumor mutational burden and germline MMR mutations, treated using anti-PD1 therapy. Methods A woman with newly diagnosed GBM (nGBM) was treated by surgery, radiotherapy, and temozolomide. The tumor recurred after 13 months leading to a second surgery and treatment with nivolumab. Whole-exome sequencing was performed on the nGBM, recurrent GBM (rGBM), and blood. Immune infiltration was investigated by immunohistochemistry and the immune response in the blood during treatment was analyzed by flow cytometry. Results High density of infiltrating CD163 + cells was found in both GBM specimens. Large numbers of CD3 + and CD8 + T cells were homogeneously distributed in the nGBM. The infiltration of CD4 + T cells and a different CD8 + T cell density were observed in the rGBM. Both GBM shared 12,431 somatic mutations, with 113 substitutions specific to the nGBM and 1,683 specific to the rGBM. Germline variants included pathogenic mutation in the MSH2 (R359S) gene, suggesting the diagnosis of Lynch syndrome. Systemic immunophenotyping revealed the generation of CD8 + T memory cells and persistent activation of CD4 + T cells. The patient is still receiving nivolumab 68 months after the second surgery. Conclusions Our observations indicate that the hypermutator phenotype associated with germinal mutations of MMR genes and abundant T-cell infiltration contributes to a durable clinical benefit sustained by a persistent and robust immune response during anti-PD1 therapy.Keywords
This publication has 43 references indexed in Scilit:
- Analysis of DNA repair gene polymorphisms in glioblastomaGene, 2014
- Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent GliomaScience, 2014
- Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patientsOncology Reports, 2013
- Cancer Genome LandscapesScience, 2013
- SAVI: a statistical algorithm for variant frequency identificationBMC Systems Biology, 2013
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- PAnnBuilder: an R package for assembling proteomic annotation dataBioinformatics, 2009
- The risk of extra‐colonic, extra‐endometrial cancer in the Lynch syndromeInternational Journal of Cancer, 2008
- Methylation of O6-Methylguanine DNA Methyltransferase and Loss of Heterozygosity on 19q and/or 17p Are Overlapping Features of Secondary Glioblastomas with Prolonged SurvivalClinical Cancer Research, 2007
- Radiotherapy plus Concomitant and Adjuvant Temozolomide for GlioblastomaThe New England Journal of Medicine, 2005