UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Wolf, Yochai; Bartok, Osnat; Patkar, Sushant; Eli, Gitit Bar; Cohen, Sapir; Litchfield, Kevin; Levy, Ronen; Jiménez-Sánchez, Alejandro; Trabish, Sophie; Lee, Joo Sang; Karathia, Hiren; Barnea, Eilon; Day, Chi-Ping; Cinnamon, Einat; Stein, Ilan; Solomon, Aryeh; Bitton, Lital; Pérez-Guijarro, Eva; Dubovik, Tania; Shen-Orr, Shai S.; Miller, Martin L.; Merlino, Glenn; Levin, Yishai; Pikarsky, Eli; Eisenbach, Lea; Admon, Arie; Swanton, Charles; Ruppin, Eytan; Samuels, Yardena

doi:10.1016/j.cell.2019.08.032

Cited by 309 publications

(310 citation statements)

References 102 publications

(151 reference statements)

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“…Mathematical modeling indicates that heterogeneity thresholds exist, beyond which T cells might fail at reducing tumor growth, consistent with recent research [14,15]. Furthermore, our simulations and analytical estimates indicate that neoantigen clonality decreases rapidly during growth, meaning that checkpoint inhibition therapy activating the immune system will not necessarily succeed.…”

Section: Combination Therapy Could Reduce Neoantigen Heterogeneitysupporting

confidence: 86%

“…This result stemming from minimal considerations might have relevance in the light of recent research on immunotherapy prognosis. Despite not considering many features of the tumor composition, the existence a catastrophic shift separating tumor growth from extinction as a function of the average neoantigen clonality resembles recent clinical studies [14,15]. To which extent is our result comparable to experimental data?…”

Section: Resultssupporting

confidence: 68%

“…Once the model is built, a diversity threshold separates cancer growth from immune control, and this threshold includes the measure of average antigen clonality, indicating the possibility for a novel biomarker for therapy prognosis and reinforcing recent experimental approaches [14,15]. Following the existence of a sharp transition governed by antigen frequency, we have studied how antigen frequency evolves prior to immunotherapy.…”

Section: Discussionmentioning

confidence: 97%

“…Analytical estimates consistent with simulations indicate a fast decay of average antigen clonality owing to neutral dynamics. This might be indicative of why, at the time of checkpoint inhibition therapy, some cancers might not respond due to large heterogeneity levels in their antigen landscape [14,15].…”

Section: Discussionmentioning

confidence: 99%

“…Once the immune system is back in place, the role of neoantigens, mutated surface proteins that elicit T cell recognition, has proven to be crucial, making genetic instability and mutational load valuable markers of eventual prognosis [9][10][11][12], and opening the door to novel therapy approaches targeting DNA stability to increase neoantigen production [13]. However, recent research highlights that not only the amount of neoantigens, but rather their heterogeneity and distribution across the tumor determines the eventual fate of immune therapies [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy

Aguadé-Gorgorió

Solé

2019

Preprint

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Following the advent of immunotherapy as a possible cure for cancer, remarkable insight has been gained on the role of mutational load and neoantigens as key ingredients in T cell recognition of malignancies. However, not all highly mutational tumors react to immune therapies, and even initial success is often followed by eventual relapse. Recent research points out that high heterogeneity in the neoantigen landscape of a tumor might be key in understanding the failure of immune surveillance. In this work we present a mathematical framework able to describe how neoantigen distributions shape the immune response. Modeling T cell reactivity as a function of antigen dominancy and distribution across a tumor indicates the existence of a diversity threshold beyond which T cells fail at controling heterogeneous cancer growth. Furthemore, an analytical estimate for the evolution of average antigen clonality indicates rapid increases in epitope heterogeneity in early malignancy growth. In this scenario, we propose that therapies targeting the tumor prior to immunotherapy can reduce neoantigen heterogeneity, and postulate the existence of a time window, before tumor relapse due to de novo resistance, rendering immunotherapy more effective. Major FindingsGenetic heterogeneity affects the immune response to an evolving tumor by shaping the neoantigen landscape of the cancer cells, and highly heterogeneous tumors seem to escape T cell recognition. Mathematical modeling predicts the existence of a well defined neoantigen diversity threshold, beyond which lymphocites are not able to counteract the growth of a population of highly heterogeneous subclones. Furthermore, evolutionary dynamics predict a fast decay of neoantigen clonality, rendering advanced tumors hard to attack at the time of immunotherapy. Within this mathematical framework we propose that targeted therapy forcing a selective pressure for resistance might as well increase neoantigen homogeneity, providing a novel possibility for combination therapy.The authors declare no potential conflicts of interest.

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Section: Combination Therapy Could Reduce Neoantigen Heterogeneitysupporting

confidence: 86%

Section: Resultssupporting

confidence: 68%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy

Aguadé-Gorgorió

Solé

2019

Preprint

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Neoantigens in cancer immunotherapy: quantity vs. quality

Wolf

Samuels

2023

Molecular Oncology

Self Cite

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Traditional immunotherapies provide clinical benefits to only a few patients with solid tumors, highlighting the urgent need for more effective approaches. Traditional immunotherapies rely on the presentation of cancer antigens, with neoantigens being highly important in this context as they are specific to malignant tissue but not healthy tissue. The quantity of neoantigens is often associated with clinical benefit, but it cannot fully explain or predict patient response. In this Viewpoint, we highlight several qualitative aspects that should be considered in neoantigen‐based therapy. We emphasize the distinction between private and recurrent neoantigens, discuss the importance of neoantigen clonality, and describe new subtypes of neopeptides that further diversify the potential of neoantigens in immunotherapy.

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A Synergistic Chemoimmunotherapy System Leveraging PD‐L1 Blocking and Bioorthogonal Prodrug Activation

Wang,

Jiang,

et al. 2024

Advanced Materials

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Novel strategies to facilitate tumor‐specific drug delivery and restore immune attacks remain challenging in overcoming the current limitations of chemoimmunotherapy. We propose an anti‐tumor chemoimmunotherapy system comprising bioorthogonal reaction‐ready group tetrazine (TZ) modified with an anti‐PD‐L1 antibody (αPD‐L1TZ) and TZ‐activatable prodrug vinyl ether‐doxorubicin (DOX‐VE) for self‐reinforced anti‐tumor chemoimmunotherapy. The αPD‐L1TZ effectively disrupts the PD‐L1/PD‐1 interaction and activates the DOX prodrug in situ through the bioorthogonal click reaction of TZ and VE. Conversely, the activated DOX upregulates PD‐L1 on the surface of tumor cells, facilitating tumor accumulation of αPD‐L1TZ and enhancing DOX‐VE activation. Further, the activated DOX‐induced immunogenic cell death of tumor cells, substantially improving the response efficiency of αPD‐L1 in an immune‐suppressive tumor microenvironment. Thus, PD‐L1 blocking and bioorthogonal in situ prodrug activation synergistically enhance the anti‐tumor efficacy of the chemoimmunotherapy system. Therefore, the system significantly enhances αPD‐L1 tumor accumulation and prodrug activation and induces a robust immunological memory effect to prevent tumor recurrence and metastasis. Thus, a feasible chemoimmunotherapy combination regimen is presented.This article is protected by copyright. All rights reserved

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UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Cited by 309 publications

References 102 publications

Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy

Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy

Neoantigens in cancer immunotherapy: quantity vs. quality

A Synergistic Chemoimmunotherapy System Leveraging PD‐L1 Blocking and Bioorthogonal Prodrug Activation

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