Association of DNA-Methylation Profiles With Immune Responses Elicited in Breast Cancer Patients Immunized With a Carbohydrate-Mimicking Peptide: A Pilot Study

Cinthia Violeta Hernandez Puente; Ping-Ching Hsu; Lora J Rogers; Fariba Jousheghany; Eric Siegel; Susan A Kadlubar; J Thaddeus Beck; Issam Makhoul; Laura F Hutchins; Thomas Kieber-Emmons; Behjatolah Monzavi-Karbassi

doi:10.3389/fonc.2020.00879

Association of DNA-Methylation Profiles With Immune Responses Elicited in Breast Cancer Patients Immunized With a Carbohydrate-Mimicking Peptide: A Pilot Study

Front Oncol. 2020 Jun 5:10:879. doi: 10.3389/fonc.2020.00879. eCollection 2020.

Authors

Cinthia Violeta Hernandez Puente^{1

2}, Ping-Ching Hsu^{3

4}, Lora J Rogers⁵, Fariba Jousheghany¹, Eric Siegel⁶, Susan A Kadlubar^{4

5}, J Thaddeus Beck⁷, Issam Makhoul^{4

8}, Laura F Hutchins^{4

8}, Thomas Kieber-Emmons^{1

4}, Behjatolah Monzavi-Karbassi^{1

4}

Affiliations

¹ Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
² UnivLyon, Université Claude Bernard Lyon 1, Lyon, France.
³ Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
⁴ Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
⁵ Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
⁶ Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
⁷ Highland Oncolgy Group, Fayetteville, AR, United States.
⁸ Division of Hematology Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.

Abstract

Immune response to a given antigen, particularly in cancer patients, is complex and is controlled by various genetic and environmental factors. Identifying biomarkers that can predict robust response to immunization is an urgent need in clinical cancer vaccine development. Given the involvement of DNA methylation in the development of lymphocytes, tumorigenicity and tumor progression, we aimed to analyze pre-vaccination DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) from breast cancer subjects vaccinated with a novel peptide-based vaccine referred to as P10s-PADRE. This pilot study was performed to evaluate whether signatures of differentially methylated (DM) loci can be developed as potential predictive biomarkers for prescreening subjects with cancer who will most likely generate an immune response to the vaccine. Genomic DNA was isolated from PBMCs of eight vaccinated subjects, and their DNA methylation profiles were determined using Infinium^® MethylationEPIC BeadChip array from Illumina. A linear regression model was applied to identify loci that were differentially methylated with respect to anti-peptide antibody titers and with IFN-γ production. The data were summarized using unsupervised-learning methods: hierarchical clustering and principal-component analysis. Pathways and networks involved were predicted by Ingenuity Pathway Analysis. We observed that the profile of DM loci separated subjects in regards to the levels of immune responses. Canonical pathways and networks related to metabolic and immunological functions were found to be involved. The data suggest that it is feasible to correlate methylation signatures in pre-treatment PBMCs with immune responses post-treatment in cancer patients going through standard-of-care chemotherapy. Larger and prospective studies that focus on DM loci in PBMCs is warranted to develop pre-screening biomarkers before BC vaccination. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier: NCT02229084.

Keywords: DNA methylation; breast cancer; cancer vaccine; immune response; pilot study.

Associated data

ClinicalTrials.gov/NCT02229084

Abstract

Associated data

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