Mutation position is an important determinant for predicting cancer neoantigens

Capietto, Aude-Hélène; Jhunjhunwala, Suchit; Pollock, Samuel B.; Lupardus, P.J.; Wong, Jim; Hänsch, Lena; Cevallos, James; Chestnut, Yajun; Fernandez, Ajay; Lounsbury, Nicolas; Nozawa, Tamaki; Singh, Manmeet; Fan, Zhiyuan; Cruz, Cecile C. de la; Phung, Qui; Taraborrelli, Lucia; Haley, Benjamin; Lill, Jennie R.; Mellman, Ira; Bourgon, Richard; Delamarre, Lélia

doi:10.1084/jem.20190179

Cited by 80 publications

(102 citation statements)

References 51 publications

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“…3 While these somatic mutations may drive epithelial cell tumorigenesis, they also serve as neoantigens to elicit tumor-reactive cytotoxic T lymphocytes (CTLs). 4 This is also consistent with the early findings that colon cancer is under constant host immunosurveillance by T cells. 5 Therefore, it might be expected that the host immune system would naturally eliminate transformed epithelial cells and early-stage tumors long before the clinically relevant tumor occurs.…”

Section: Introductionsupporting

confidence: 90%

p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

Lu¹,

Klement²,

Smith³

et al. 2020

J Immunother Cancer

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BackgroundNF-κB is a key link between inflammation and cancer. Previous studies of NF-κB have largely focused on tumor cells, and the intrinsic function of NF-κB in T cells in tumor development and response to immunotherapy is largely unknown. We aimed at testing the hypothesis that NF-κB1 (p50) activation in T cells underlies human colon cancer immune escape and human cancer non-response to anti-PD-1 immunotherapy.MethodsWe screened NF-κB activation in human colon carcinoma and used mouse models to determine p50 function in tumor cells and immune cells. RNA-Seq was used to identify p50 target genes. p50 binding to target gene promoters were determined by electrophoresis mobility shift assay and chromatin immunoprecipitation. A p50 activation score was generated from gene expression profiling and used to link p50 activation to T-cell activation and function pre-nivolumab and post-nivolumab immunotherapy in human patients with cancer.Resultsp50 is the dominant form of NF-κB that is highly activated in immune cells in the human colorectal carcinoma microenvironment and neighboring non-neoplastic colon epithelial cells. Tumor cell intrinsic p50 signaling and T-cell intrinsic p50 signaling exert opposing functions in tumor growth control in vivo. Deleting Nfkb1 in tumor cells increased whereas in T cells decreased tumor growth in preclinical mouse models. Gene expression profiling identified Gzmb as a p50 target in T cells. p50 binds directly to a previously uncharacterized κB sequence at the Gzmb promoter in T cells, resulting in repression of Gzmb expression in tumor-infiltrating cytotoxic T lymphocytes (CTLs) to induce a dysfunctional CTL phenotype to promote tumor immune escape. p50 activation is inversely correlated with both GZMB expression and T-cell tumor infiltration in human colorectal carcinoma. Furthermore, nivolumab immunotherapy decreased p50 activation and increased GZMB expression in human patients with melanoma.ConclusionsInflammation activates p50 that binds to the Gzmb promoter to repress granzyme B expression in T cells, resulting in CTL dysfunction to confer tumor immune escape and decreased response to anti-PD-1 immunotherapy.

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Section: Introductionsupporting

confidence: 90%

p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

Lu¹,

Klement²,

Smith³

et al. 2020

J Immunother Cancer

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“…Ten previously described mutated tumor neoantigens, including Adpgk, served as vaccine targets. 35 Mice received four weekly doses of the vaccine starting 11 days after tumor inoculation, with pre-or post-treatment with Dexa ( Figure 5(e)). Tumor growth was significantly inhibited by the neoantigen vaccine, resulting in tumor regression in all mice ( Figure 5(f)).…”

Section: Resultsmentioning

confidence: 99%

Dexamethasone premedication suppresses vaccine-induced immune responses against cancer

Vormehr

Lehar²,

Kranz

et al. 2020

OncoImmunology

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Glucocorticosteroids (GCS) have an established role in oncology and are administered to cancer patients in routine clinical care and in drug development trials as co-medication. Given their strong immunesuppressive activity, GCS may interfere with immune-oncology drugs. We are developing a therapeutic cancer vaccine, which is based on a liposomal formulation of tumor-antigen encoding RNA (RNA-LPX) and induces a strong T-cell response both in mice as well as in humans. In this study, we investigated in vivo in mice and in human PBMCs the effect of the commonly used long-acting GCS Dexamethasone (Dexa) on the efficacy of this vaccine format, with a particular focus on antigen-specific T-cell immune responses. We show that Dexa, when used as premedication, substantially blunts RNA-LPX vaccine-mediated immune effects. Premedication with Dexa inhibits vaccine-dependent induction of serum cytokines and chemokines and reduces both the number and activation of splenic conventional dendritic cells (cDC) expressing vaccineencoded antigens. Consequently, priming of functional effector T cells and therapeutic activity is significantly impaired. Interestingly, responses are less impacted when Dexa is administered post-vaccination. Consistent with this observation, although many inflammatory cytokines are reduced, IFNα, a key cytokine in T-cell priming, is less impacted and antigen expression by cDCs is intact. These findings warrant special caution when combining GCS with immune therapies relying on priming and activation of antigen-specific T cells and suggest that careful sequencing of these treatments may preserve T-cell induction.

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“…These findings suggest that while structural homology may inform cross-recognition potential of peptides having the same structural configuration, current methods are suboptimal in predicting polyspecificity across different classes. Moreover, amino acid mutations at positions distant from direct recognition sites may also have a substantial effect on TCR:pMHC interaction e.g., change in binding parameters and/or structural conformation, and can only be validated by experimentation (163). Altogether these may imply an immense breadth of promiscuity beyond our expectations based on current understanding.…”

Section: Features From Structural Modelingmentioning

confidence: 99%

Predicting Cross-Reactivity and Antigen Specificity of T Cell Receptors

et al. 2020

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Adaptive immune recognition is mediated by specific interactions between heterodimeric T cell receptors (TCRs) and their cognate peptide-MHC (pMHC) ligands, and the methods to accurately predict TCR:pMHC interaction would have profound clinical, therapeutic and pharmaceutical applications. Herein, we review recent developments in predicting cross-reactivity and antigen specificity of TCR recognition. We discuss current experimental and computational approaches to investigate cross-reactivity and antigen-specificity of TCRs and highlight how integrating kinetic, biophysical and structural features may offer valuable insights in modeling immunogenicity. We further underscore the close interrelationship of these two interconnected notions and the need to investigate each in the light of the other for a better understanding of T cell responsiveness for the effective clinical applications.

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Mutation position is an important determinant for predicting cancer neoantigens

Cited by 80 publications

References 51 publications

p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

Dexamethasone premedication suppresses vaccine-induced immune responses against cancer

Predicting Cross-Reactivity and Antigen Specificity of T Cell Receptors

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