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Immunogenicity and Immune Silence in Human Cancer

49 Pages Posted: 8 Apr 2019 Sneak Peek Status: Under Review

See all articles by Mark Yarmarkovich

Mark Yarmarkovich

Children’s Hospital of Philadelphia - Division of Oncology; Children’s Hospital of Philadelphia - Center for Childhood Cancer Research; University of Pennsylvania - Perelman School of Medicine

Alvin Farrel

Children’s Hospital of Philadelphia - Division of Oncology; Children’s Hospital of Philadelphia - Center for Childhood Cancer Research

Artemio Sison III

Children’s Hospital of Philadelphia - Department of Biomedical and Health Informatics

Moreno di Marco

University of Tuebingen

Pichai Raman

Children’s Hospital of Philadelphia - Department of Biomedical and Health Informatics; Children’s Hospital of Philadelphia - The Center for Data Driven Discovery in Biomedicine

Joshua L. Parris

University of Pennsylvania - Perelman School of Medicine

Dimitrios Monos

Children’s Hospital of Philadelphia - Department of Pathology and Lab Medicine

Hongzhe Lee

University of Pennsylvania - Perelman School of Medicine

Stefan Stevanovic

University of Tuebingen

John M. Maris

Children’s Hospital of Philadelphia - Division of Oncology; Children’s Hospital of Philadelphia - Center for Childhood Cancer Research; University of Pennsylvania - Perelman School of Medicine

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Abstract

Despite recent advances in cancer immunotherapy, the process of immunoediting early in tumorigenesis remains obscure. Here, we employ a mathematical model that utilizes the Cancer Genome Atlas (TCGA) data to elucidate the contribution of individual mutations and HLA alleles to the immunoediting process. We find that common cancer mutations including BRAF-V600E and KRAS-G12D are predicted to bind none of the common HLA alleles, and are thus “immunogenically silent” in the human population. We identify regions of proteins that are not presented by HLA at a population scale, coinciding with frequently mutated hotspots in cancer, and other protein regions broadly presented across the population in which few mutations occur. We also find that 9/29 common HLA alleles contribute disproportionately to the immunoediting of early oncogenic mutations. These data provide insights into immune evasion of common driver mutations and a molecular basis for the association of particular HLA genotypes with cancer susceptibility.

Keywords: Immunoediting, neoantigens, HLA, cancer susceptibility, KRAS, BRAF

Suggested Citation

Yarmarkovich, Mark and Farrel, Alvin and III, Artemio Sison and Marco, Moreno di and Raman, Pichai and Parris, Joshua L. and Monos, Dimitrios and Lee, Hongzhe and Stevanovic, Stefan and Maris, John M., Immunogenicity and Immune Silence in Human Cancer (April 6, 2019). Available at SSRN: https://ssrn.com/abstract=3367154 or http://dx.doi.org/10.2139/ssrn.3367154
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Mark Yarmarkovich

Children’s Hospital of Philadelphia - Division of Oncology

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Children’s Hospital of Philadelphia - Center for Childhood Cancer Research

34th St and Civic Center Blvd
Philadelphia, PA 19104
United States

University of Pennsylvania - Perelman School of Medicine

423 Guardian Drive
Philadelphia, PA 19104
United States

Alvin Farrel

Children’s Hospital of Philadelphia - Division of Oncology

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Children’s Hospital of Philadelphia - Center for Childhood Cancer Research

34th St and Civic Center Blvd
Philadelphia, PA 19104
United States

Artemio Sison III

Children’s Hospital of Philadelphia - Department of Biomedical and Health Informatics

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Moreno di Marco

University of Tuebingen

Wilhelmstr. 19
72074 Tuebingen, Baden Wuerttemberg 72074
Germany

Pichai Raman

Children’s Hospital of Philadelphia - Department of Biomedical and Health Informatics

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Children’s Hospital of Philadelphia - The Center for Data Driven Discovery in Biomedicine

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Joshua L. Parris

University of Pennsylvania - Perelman School of Medicine

423 Guardian Drive
Philadelphia, PA 19104
United States

Dimitrios Monos

Children’s Hospital of Philadelphia - Department of Pathology and Lab Medicine

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Hongzhe Lee

University of Pennsylvania - Perelman School of Medicine

423 Guardian Drive
Philadelphia, PA 19104
United States

Stefan Stevanovic

University of Tuebingen

Wilhelmstr. 19
72074 Tuebingen, Baden Wuerttemberg 72074
Germany

John M. Maris (Contact Author)

Children’s Hospital of Philadelphia - Division of Oncology ( email )

34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4399
United States

Children’s Hospital of Philadelphia - Center for Childhood Cancer Research ( email )

34th St and Civic Center Blvd
Philadelphia, PA 19104
United States

University of Pennsylvania - Perelman School of Medicine ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

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