Rejection of immunogenic tumor clones is limited by clonal fraction.

Ron S Gejman,Krysta Dikun,Andrea Schietinger,Abraham Ari Hakimi,Aaron Y Chang,David A Scheinberg,Heather F Jones

doi:10.7554/elife.41090

Ron S Gejman, Krysta Dikun + Show 5 more

Open Access

https://doi.org/10.7554/elife.41090

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Journal: eLife	Publication Date: Nov 30, 2018
Citations: 96	License type: CC BY 4.0

Affiliation: Cornell University, Memorial Sloan Kettering Cancer Center

Abstract

Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new 'PresentER' antigen presentation platform. Surprisingly, we show that immunogenic tumor antigens do not lead to immune-mediated cell rejection when the fraction of cells bearing each antigen ('clonal fraction') is low. Moreover, the clonal fraction necessary to lead to rejection of immunogenic tumor subclones depends on the antigen. These data indicate that tumor neoantigen heterogeneity has an underappreciated impact on immune elimination of cancer cells and has implications for the design of immunotherapeutics such as cancer vaccines.

Highlights

Human cancers bear uniquely distinguishable features on the surface of their cells in the form of neoantigens, which are peptides derived from mutated, foreign or oncofetal proteins that are presented in complex with major histocompatibility complex I (MHC-I) molecules
As previously described (Gejman, 2018a), Transporter associated with antigen presentation (Tap) deficient cell lines expressing PresentER antigen minigenes lead to surface presentation of the encoded MHC-I peptide, detectable by multiple modalities, including fluorescently labeled antibodies directed to specific MHC-I ligands, mass spectrometry based immunopeptidomics and antigen-specific T cell reactivity
To demonstrate the applicability of PresentER antigen minigenes to study MHC-I ligand immunogenicity, we first asked if cancer cells encoding known immunogenic (mouse Tyrp1/gp75 TAYRYHLL W223A,H224Y (Dyall et al, 1998); mouse Ddx5/p68 SNFVFAGI S551F (Dubey et al, 1997); synthetic SIYRYYGL (Udaka et al, 1996); synthetic VTFVFAGL (Dubey et al, 1997); chicken ovalbumin SIINFEKL) or non-immunogenic (mouse Serpinf1/Pedf MSIIFFLPL (Wang et al, 2006); scrambled chicken ovalbumin FEKIILSN; mouse Ndufa4/dEV8 EQYKFYSV (Holler et al, 2003); mouse Ddx5/p68 SNFVSAGI (Dubey et al, 1997); mouse Tyrp1/gp75 TWHRYHLL (Dyall et al, 1998); Mouse Trp2 SVYDFFVWL) MHC-I ligands would be rejected by wildtype (WT) animals

Summary

Introduction

Human cancers bear uniquely distinguishable features on the surface of their cells in the form of neoantigens, which are peptides derived from mutated, foreign or oncofetal proteins that are presented in complex with major histocompatibility complex I (MHC-I) molecules. These short, 8–11 amino acid fragments mark cancer cells and activate potent immune responses that can lead to effective anti-cancer therapy (Tran et al, 2014; Rosenberg and Restifo, 2015; Zacharakis et al, 2018). Antigen-specific immune effects are limited during early tumorigenesis, which has implications for the emergence and outgrowth of immunogenic tumors

Results

Discussion

Materials and methods

F30 CA200327