Humoral immunoprofiling identifies novel biomarkers and an immune suppressive autoantibody phenotype at the site of disease in pancreatic ductal adenocarcinoma

Pamela Winnie M Maimela; Muneerah Smith; Andrew J M Nel; Suba Dharshanan P Bernam; Eduard G Jonas; Jonathan M Blackburn

doi:10.3389/fonc.2024.1330419

Humoral immunoprofiling identifies novel biomarkers and an immune suppressive autoantibody phenotype at the site of disease in pancreatic ductal adenocarcinoma

Front Oncol. 2024 Feb 21:14:1330419. doi: 10.3389/fonc.2024.1330419. eCollection 2024.

Authors

Pamela Winnie M Maimela¹, Muneerah Smith¹, Andrew J M Nel¹, Suba Dharshanan P Bernam², Eduard G Jonas³, Jonathan M Blackburn^{1

2

4}

Affiliations

¹ Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
² Sengenics Corporation, Kuala Lumpur, Malaysia.
³ Department of Surgery, Gastroenterology Unit, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
⁴ Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer, with minimal response to therapeutic intervention and with 85% of cases diagnosed at an advanced stage due to lack of early symptoms, highlighting the importance of understanding PDAC immunology in greater detail. Here, we applied an immunoproteomic approach to investigate autoantibody responses against cancer-testis and tumor-associated antigens in PDAC using a high-throughput multiplexed protein microarray platform, comparing humoral immune responses in serum and at the site of disease in order to shed new light on immune responses in the tumor microenvironment. We simultaneously quantified serum or tissue IgG and IgA antibody isotypes and subclasses in a cohort of PDAC, disease control and healthy patients, observing inter alia that subclass utilization in tumor tissue samples was predominantly immune suppressive IgG4 and inflammatory IgA2, contrasting with predominant IgG3 and IgA1 subclass utilization in matched sera and implying local autoantibody production at the site of disease in an immune-tolerant environment. By comparison, serum autoantibody subclass profiling for the disease controls identified IgG4, IgG1, and IgA1 as the abundant subclasses. Combinatorial analysis of serum autoantibody responses identified panels of candidate biomarkers. The top IgG panel included ACVR2B, GAGE1, LEMD1, MAGEB1 and PAGE1 (sensitivity, specificity and AUC values of 0.933, 0.767 and 0.906). Conversely, the top IgA panel included AURKA, GAGE1, MAGEA10, PLEKHA5 and XAGE3aV1 (sensitivity, specificity, and AUC values of 1.000, 0.800, and 0.954). Assessment of antigen-specific serum autoantibody glycoforms revealed abundant sialylation on IgA in PDAC, consistent with an immune suppressive IgA response to disease.

Keywords: antibody glycosylation; autoantibody biomarkers; cancer testis antigen; pancreatic ductal adenocarcinoma; protein microarray.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by a grant to JB from the Andrea Fine Foundation, South Africa.PM thanks the Council of Scientific and Industrial Research (CSIR) South Africa for a Masters bursary.