Peroxynitrite in the tumor microenvironment changes the profile of antigens allowing escape from cancer immunotherapy

Tcyganov, Evgenii N.; Sanseviero, Emilio; Marvel, Douglas; Tang, Hsin‐Yao; Hembach, Peter; Speicher, David W.; Zhang, Qianfei; Donthireddy, Laxminarasimha; Mostafa, Ali; Tsyganova, Sabina; Писарев, В. С.; Laufer, Terri M.; Ignatov, Dmitriy; Ferrone, Soldano; Meyer, Christiane; Hajjami, Hélène Maby–El; Speiser, Daniel E.; Altiok, Sooner; Antonia, Scott; Xu, Xiaowei; Xu, Wei; Zheng, Cathy; Schuchter, Lynn M.; Amaravadi, Ravi K.; Mitchell, Tara C.; Karakousis, Giorgos C.; Yuan, Zhe; Montaner, Luis J.; Celis, Esteban; Gabrilovich, Dmitry I.

doi:10.1016/j.ccell.2022.09.001

Cited by 26 publications

(14 citation statements)

References 42 publications

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“…The oxidants like peroxynitrite generated by myeloid cells in tumor microenvironment (TME) inhibit the activity of proteasome, thereby decreasing the production of MHC-I peptides. 193,194 Protein splicing significantly increases the proteome complexity of malignancies, which alters the hierarchy of antigenic epitopes. 195,196 Studies have also revealed that the proteasome can produce novel immunoreactive spliced epitopes (splicetopes) by fusing with peptide fragments excised by reverse proteolysis during proteasome-catalyzed peptide splicing (PCPS), which differ from the original substrate protein sequence.…”

Section: Transcriptomic Variantsmentioning

confidence: 99%

Neoantigens: promising targets for cancer therapy

Xie

Shen

Gao

et al. 2023

Sig Transduct Target Ther

317

150

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Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.

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Section: Transcriptomic Variantsmentioning

confidence: 99%

Neoantigens: promising targets for cancer therapy

Xie

Shen

Gao

et al. 2023

Sig Transduct Target Ther

317

150

View full text Add to dashboard Cite

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“…A recent study demonstrated that NCX-4016 (nitroaspirin), a compound that blocks intratumoral production of PNT, can synergize with anti-PD-1 IgG to promote antitumor activity . Here, we identified dasatinib as a potent alternative inhibitor of production of PNT during ADCP.…”

Section: Discussionmentioning

confidence: 92%

“…In mouse models of cancer, PNT produced by granulocytic MDSCs has been shown to inhibit T cell function, and MDSCs contribute to nitration of Tyr394 of the tyrosine kinase Lck in T cells, blocking phosphorylation at that site and leading to downstream inhibition of the murine T cell receptor (TCR). PNT can also affect binding of antigenic peptides to MHC proteins on tumors , and affect T cell migration by modifying chemokines . Because of the extremely short half-life of PNT in cells (estimated to be 10–20 milliseconds at pH 7.4), previous studies of PNT in cancer have generally been limited to indirect detection of nitrotyrosine residues of modified proteins …”

mentioning

confidence: 99%

Fluorescent Detection of Peroxynitrite Produced by Myeloid-Derived Suppressor Cells in Cancer and Inhibition by Dasatinib

Carlson

Savardekar

et al. 2023

ACS Pharmacol. Transl. Sci.

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Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that expand dramatically in many cancer patients. This expansion contributes to immunosuppression in cancer and reduces the efficacy of immune-based cancer therapies. One mechanism of immunosuppression mediated by MDSCs involves production of the reactive nitrogen species peroxynitrite (PNT), where this strong oxidant inactivates immune effector cells through destructive nitration of tyrosine residues in immune signal transduction pathways. As an alternative to analysis of nitrotyrosines indirectly generated by PNT, we used an endoplasmic reticulum (ER)-targeted fluorescent sensor termed PS3 that allows direct detection of PNT produced by MDSCs. When the MDSC-like cell line MSC2 and primary MDSCs from mice and humans were treated with PS3 and antibody-opsonized TentaGel microspheres, phagocytosis of these beads led to production of PNT and generation of a highly fluorescent product. Using this method, we show that splenocytes from a EMT6 mouse model of cancer, but not normal control mice, produce high levels of PNT due to elevated numbers of granulocytic (PMN) MDSCs. Similarly, peripheral blood mononuclear cells (PBMCs) isolated from blood of human melanoma patients produced substantially higher levels of PNT than healthy human volunteers, coincident with higher peripheral MDSC levels. The kinase inhibitor dasatinib was found to potently block the production of PNT both by inhibiting phagocytosis in vitro and by reducing the number of granulocytic MDSCs in mice in vivo, providing a chemical tool to modulate the production of this reactive nitrogen species (RNS) in the tumor microenvironment.

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“… 4 , 5 , 6 As tumor cells could also be the target of PNT nitration, Tcyganov et al. 1 sought to explore the direct effect of PNT on the MHC class I peptidome presented by tumors and whether it influences response to immunotherapy.…”

Section: Main Textmentioning

confidence: 99%

“… A study by Tcyganov et al. 1 demonstrates that peroxynitrite, an oxidant abundant in the tumor microenvironment, changes the repertoire of MHC class I peptides presented by tumors and limits immune recognition. Peroxynitrite inhibition in combination with immune checkpoint blockade enhances efficacy preclinically.…”

mentioning

confidence: 99%