CD91 on dendritic cells governs immunosurveillance of nascent, emerging tumors

Abigail L Sedlacek; Theodore P Younker; Yu Jerry Zhou; Lisa Borghesi; Tatiana Shcheglova; Ion I Mandoiu; Robert J Binder

doi:10.1172/jci.insight.127239

CD91 on dendritic cells governs immunosurveillance of nascent, emerging tumors

JCI Insight. 2019 Apr 4;4(7):e127239. doi: 10.1172/jci.insight.127239.

Authors

Abigail L Sedlacek¹, Theodore P Younker², Yu Jerry Zhou³, Lisa Borghesi¹, Tatiana Shcheglova⁴, Ion I Mandoiu⁵, Robert J Binder¹

Affiliations

¹ Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
² Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington, USA.
³ Targeted Therapeutics Discovery Unit, Pfizer, Pearl River, New York, USA.
⁴ Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, USA.
⁵ Department of Computer Science and Engineering, University of Connecticut, Storrs, Connecticut, USA.

Abstract

The immune system detects aberrant, premalignant cells and eliminates them before the development of cancer. Immune cells, including T cells, have been shown to be critical components in eradicating these aberrant cells, and when absent in the host, incidence of cancer increases. Here, we show that CD91, a receptor expressed on antigen-presenting cells, is required for priming immune responses to nascent, emerging tumors. In the absence of CD91, effector immune responses are subdued, and tumor incidence and progression are amplified. We also show that, consequently, tumors that arise in the absence of CD91 express neo-epitopes with indices that are indicative of greater immunogenicity. Polymorphisms in human CD91 that are expected to affect ligand binding are shown to influence antitumor immune responses in cancer patients. This study presents a molecular mechanism for priming immune responses to nascent, emerging tumors that becomes a predictor of cancer susceptibility and progression.

Keywords: Adaptive immunity; Antigen presentation; Cancer; Immunology.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigen Presentation / genetics
Antigens, Neoplasm / immunology
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / immunology*
Carcinoma, Squamous Cell / pathology
Cross-Priming / genetics
Dendritic Cells / immunology
Dendritic Cells / metabolism*
Epitope Mapping
Epitopes, T-Lymphocyte / immunology
Exome Sequencing
Female
Humans
Immunologic Surveillance / genetics
Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
Low Density Lipoprotein Receptor-Related Protein-1 / immunology
Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
Lung Neoplasms / genetics
Lung Neoplasms / immunology*
Lung Neoplasms / pathology
Melanoma / genetics
Melanoma / immunology*
Melanoma / pathology
Methylcholanthrene / administration & dosage
Methylcholanthrene / toxicity
Mice
Mice, Knockout
Neoplasms, Experimental / chemically induced
Neoplasms, Experimental / immunology
Neoplasms, Experimental / pathology
Polymorphism, Single Nucleotide
Protein Domains / genetics
Protein Stability
Skin Neoplasms / genetics
Skin Neoplasms / immunology*
Skin Neoplasms / pathology

Substances

Antigens, Neoplasm
Epitopes, T-Lymphocyte
LRP1 protein, human
Low Density Lipoprotein Receptor-Related Protein-1
Lrp1 protein, mouse
Methylcholanthrene

Abstract

Publication types

MeSH terms

Substances

Grants and funding