Antitumor reactive T-cell responses are enhanced in vivo by DAMP prothymosin alpha and its C-terminal decapeptide

Anastasios I. Birmpilis; Chrysoula Evangelia Karachaliou; Pinelopi Samara; Kyriaki Ioannou; Platon Selemenakis; Ioannis V. Kostopoulos; Nadia Kavrochorianou; Hubert Kalbacher; Evangelia Livaniou; Sylva Haralambous; Athanasios Kotsinas; Farzin Farzaneh; Ioannis P. Trougakos; Wolfgang Voelter; Meletios Athanasios Dimopoulos; Aristotelis Bamias; Ourania Tsitsilonis

doi:10.3390/cancers11111764

Antitumor reactive T-cell responses are enhanced in vivo by DAMP prothymosin alpha and its C-terminal decapeptide

Anastasios I. Birmpilis, Chrysoula Evangelia Karachaliou, Pinelopi Samara, Kyriaki Ioannou, Platon Selemenakis, Ioannis V. Kostopoulos, Nadia Kavrochorianou, Hubert Kalbacher, Evangelia Livaniou, Sylva Haralambous, Athanasios Kotsinas, Farzin Farzaneh, Ioannis P. Trougakos, Wolfgang Voelter, Meletios Athanasios Dimopoulos, Aristotelis Bamias, Ourania Tsitsilonis^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

Prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) were shown to pleiotropically enhance innate and adaptive immune responses. Their activities have been broadly studied in vitro, focusing primarily on the restoration of the deficient immunoreactivity of cancer patients’ leukocytes. Previously, we showed that proTα and proTα(100–109) act as danger-associated molecular patterns (DAMPs), ligate Toll-like receptor-4, signal through TRIF-and MyD88-dependent pathways, promote the maturation of dendritic cells and elicit T-helper type 1 (Th1) immune responses in vitro, leading to the optimal priming of tumor antigen-reactive T-cell functions. Herein, we assessed their activity in a preclinical melanoma model. Immunocompetent mice bearing B16.F1 tumors were treated with two cycles of proTα or proTα(100–109) together with a B16.F1-derived peptide vaccine. Coadministration of proTα or proTα(100–109) and the peptide vaccine suppressed melanoma-cell proliferation, as evidenced by reduced tumor-growth rates. Higher melanoma infiltration by CD3+ T cells was observed, whereas ex vivo analysis of mouse total spleen cells verified the in vivo induction of melanoma-reactive cytotoxic responses. Additionally, increased levels of proinflammatory and Th1-type cytokines were detected in mouse serum. We propose that, in the presence of tumor antigens, DAMPs proTα and proTα(100–109) induce Th1-biased immune responses in vivo. Their adjuvant ability to orchestrate antitumor immunoreactivities can eventually be exploited therapeutically in humans.

Original language	English
Article number	1764
Journal	Cancers
Volume	11
Issue number	11
DOIs	https://doi.org/10.3390/cancers11111764
Publication status	Published - 1 Nov 2019

Keywords

Adjuvant
Antitumor peptide vaccine
Biologic response modifier
Danger-associated molecular pattern—DAMP
Immunoreactive decapeptide
In vivo melanoma model
Proinflammatory cytokine
Prothymosin α
Th1-type cytokine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers11111764

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Birmpilis, A. I., Karachaliou, C. E., Samara, P., Ioannou, K., Selemenakis, P., Kostopoulos, I. V., Kavrochorianou, N., Kalbacher, H., Livaniou, E., Haralambous, S., Kotsinas, A., Farzaneh, F., Trougakos, I. P., Voelter, W., Dimopoulos, M. A., Bamias, A., & Tsitsilonis, O. (2019). Antitumor reactive T-cell responses are enhanced in vivo by DAMP prothymosin alpha and its C-terminal decapeptide. Cancers, 11(11), Article 1764. https://doi.org/10.3390/cancers11111764

@article{8efaeb49a9ea496299bb97c5ad9b3624,

title = "Antitumor reactive T-cell responses are enhanced in vivo by DAMP prothymosin alpha and its C-terminal decapeptide",

abstract = "Prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) were shown to pleiotropically enhance innate and adaptive immune responses. Their activities have been broadly studied in vitro, focusing primarily on the restoration of the deficient immunoreactivity of cancer patients{\textquoteright} leukocytes. Previously, we showed that proTα and proTα(100–109) act as danger-associated molecular patterns (DAMPs), ligate Toll-like receptor-4, signal through TRIF-and MyD88-dependent pathways, promote the maturation of dendritic cells and elicit T-helper type 1 (Th1) immune responses in vitro, leading to the optimal priming of tumor antigen-reactive T-cell functions. Herein, we assessed their activity in a preclinical melanoma model. Immunocompetent mice bearing B16.F1 tumors were treated with two cycles of proTα or proTα(100–109) together with a B16.F1-derived peptide vaccine. Coadministration of proTα or proTα(100–109) and the peptide vaccine suppressed melanoma-cell proliferation, as evidenced by reduced tumor-growth rates. Higher melanoma infiltration by CD3+ T cells was observed, whereas ex vivo analysis of mouse total spleen cells verified the in vivo induction of melanoma-reactive cytotoxic responses. Additionally, increased levels of proinflammatory and Th1-type cytokines were detected in mouse serum. We propose that, in the presence of tumor antigens, DAMPs proTα and proTα(100–109) induce Th1-biased immune responses in vivo. Their adjuvant ability to orchestrate antitumor immunoreactivities can eventually be exploited therapeutically in humans.",

keywords = "Adjuvant, Antitumor peptide vaccine, Biologic response modifier, Danger-associated molecular pattern—DAMP, Immunoreactive decapeptide, In vivo melanoma model, Proinflammatory cytokine, Prothymosin α, Th1-type cytokine",

author = "Birmpilis, {Anastasios I.} and Karachaliou, {Chrysoula Evangelia} and Pinelopi Samara and Kyriaki Ioannou and Platon Selemenakis and Kostopoulos, {Ioannis V.} and Nadia Kavrochorianou and Hubert Kalbacher and Evangelia Livaniou and Sylva Haralambous and Athanasios Kotsinas and Farzin Farzaneh and Trougakos, {Ioannis P.} and Wolfgang Voelter and Dimopoulos, {Meletios Athanasios} and Aristotelis Bamias and Ourania Tsitsilonis",

year = "2019",

month = nov,

day = "1",

doi = "10.3390/cancers11111764",

language = "English",

volume = "11",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "11",

}

Birmpilis, AI, Karachaliou, CE, Samara, P, Ioannou, K, Selemenakis, P, Kostopoulos, IV, Kavrochorianou, N, Kalbacher, H, Livaniou, E, Haralambous, S, Kotsinas, A, Farzaneh, F, Trougakos, IP, Voelter, W, Dimopoulos, MA, Bamias, A & Tsitsilonis, O 2019, 'Antitumor reactive T-cell responses are enhanced in vivo by DAMP prothymosin alpha and its C-terminal decapeptide', Cancers, vol. 11, no. 11, 1764. https://doi.org/10.3390/cancers11111764

TY - JOUR

T1 - Antitumor reactive T-cell responses are enhanced in vivo by DAMP prothymosin alpha and its C-terminal decapeptide

AU - Birmpilis, Anastasios I.

AU - Karachaliou, Chrysoula Evangelia

AU - Samara, Pinelopi

AU - Ioannou, Kyriaki

AU - Selemenakis, Platon

AU - Kostopoulos, Ioannis V.

AU - Kavrochorianou, Nadia

AU - Kalbacher, Hubert

AU - Livaniou, Evangelia

AU - Haralambous, Sylva

AU - Kotsinas, Athanasios

AU - Farzaneh, Farzin

AU - Trougakos, Ioannis P.

AU - Voelter, Wolfgang

AU - Dimopoulos, Meletios Athanasios

AU - Bamias, Aristotelis

AU - Tsitsilonis, Ourania

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) were shown to pleiotropically enhance innate and adaptive immune responses. Their activities have been broadly studied in vitro, focusing primarily on the restoration of the deficient immunoreactivity of cancer patients’ leukocytes. Previously, we showed that proTα and proTα(100–109) act as danger-associated molecular patterns (DAMPs), ligate Toll-like receptor-4, signal through TRIF-and MyD88-dependent pathways, promote the maturation of dendritic cells and elicit T-helper type 1 (Th1) immune responses in vitro, leading to the optimal priming of tumor antigen-reactive T-cell functions. Herein, we assessed their activity in a preclinical melanoma model. Immunocompetent mice bearing B16.F1 tumors were treated with two cycles of proTα or proTα(100–109) together with a B16.F1-derived peptide vaccine. Coadministration of proTα or proTα(100–109) and the peptide vaccine suppressed melanoma-cell proliferation, as evidenced by reduced tumor-growth rates. Higher melanoma infiltration by CD3+ T cells was observed, whereas ex vivo analysis of mouse total spleen cells verified the in vivo induction of melanoma-reactive cytotoxic responses. Additionally, increased levels of proinflammatory and Th1-type cytokines were detected in mouse serum. We propose that, in the presence of tumor antigens, DAMPs proTα and proTα(100–109) induce Th1-biased immune responses in vivo. Their adjuvant ability to orchestrate antitumor immunoreactivities can eventually be exploited therapeutically in humans.

AB - Prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) were shown to pleiotropically enhance innate and adaptive immune responses. Their activities have been broadly studied in vitro, focusing primarily on the restoration of the deficient immunoreactivity of cancer patients’ leukocytes. Previously, we showed that proTα and proTα(100–109) act as danger-associated molecular patterns (DAMPs), ligate Toll-like receptor-4, signal through TRIF-and MyD88-dependent pathways, promote the maturation of dendritic cells and elicit T-helper type 1 (Th1) immune responses in vitro, leading to the optimal priming of tumor antigen-reactive T-cell functions. Herein, we assessed their activity in a preclinical melanoma model. Immunocompetent mice bearing B16.F1 tumors were treated with two cycles of proTα or proTα(100–109) together with a B16.F1-derived peptide vaccine. Coadministration of proTα or proTα(100–109) and the peptide vaccine suppressed melanoma-cell proliferation, as evidenced by reduced tumor-growth rates. Higher melanoma infiltration by CD3+ T cells was observed, whereas ex vivo analysis of mouse total spleen cells verified the in vivo induction of melanoma-reactive cytotoxic responses. Additionally, increased levels of proinflammatory and Th1-type cytokines were detected in mouse serum. We propose that, in the presence of tumor antigens, DAMPs proTα and proTα(100–109) induce Th1-biased immune responses in vivo. Their adjuvant ability to orchestrate antitumor immunoreactivities can eventually be exploited therapeutically in humans.

KW - Adjuvant

KW - Antitumor peptide vaccine

KW - Biologic response modifier

KW - Danger-associated molecular pattern—DAMP

KW - Immunoreactive decapeptide

KW - In vivo melanoma model

KW - Proinflammatory cytokine

KW - Prothymosin α

KW - Th1-type cytokine

UR - http://www.scopus.com/inward/record.url?scp=85074701084&partnerID=8YFLogxK

U2 - 10.3390/cancers11111764

DO - 10.3390/cancers11111764

M3 - Article

AN - SCOPUS:85074701084

SN - 2072-6694

VL - 11

JO - Cancers

JF - Cancers

IS - 11

M1 - 1764

ER -

Antitumor reactive T-cell responses are enhanced in vivo by DAMP prothymosin alpha and its C-terminal decapeptide

Abstract

Keywords

UN SDGs

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