Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy

Gohar S. Manzar; Molly B.El Alam; Erica J. Lynn; Tatiana V. Karpinets; Timothy Harris; David Lo; Kyoko Yoshida-Court; Tatiana Cisneros Napravnik; Julie Sammouri; Daniel Lin; Lauren M. Andring; Julianna Bronk; Xiaogang Wu; Travis T. Sims; Geena Mathew; Kathleen M. Schmeler; Patricia J Eifel; Anuja Jhingran; Lilie L. Lin; Melissa M. Joyner; Jianhua Zhang; Andrew Futreal; Ann H. Klopp; Lauren E. Colbert

doi:10.1016/j.brachy.2023.10.007

Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy

Gohar S. Manzar, Molly B.El Alam, Erica J. Lynn, Tatiana V. Karpinets, Timothy Harris, David Lo, Kyoko Yoshida-Court, Tatiana Cisneros Napravnik, Julie Sammouri, Daniel Lin, Lauren M. Andring, Julianna Bronk, Xiaogang Wu, Travis T. Sims, Geena Mathew, Kathleen M. Schmeler, Patricia J Eifel, Anuja Jhingran, Lilie L. Lin, Melissa M. JoynerJianhua Zhang, Andrew Futreal, Ann H. Klopp, Lauren E. Colbert

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

Abstract

Background: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. Methods: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020–1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-β/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. Results: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2–50.2 fold-increase from baseline), frequency (1.2–1.7), rearrangements (1.2–40.2), and clonality (1.2–15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. Conclusion: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

Original language	English (US)
Pages (from-to)	123-135
Number of pages	13
Journal	Brachytherapy
Volume	23
Issue number	2
DOIs	https://doi.org/10.1016/j.brachy.2023.10.007
State	Published - Mar 2024

Keywords

Antigen-specific immunity
Brachytherapy
Cervical cancer
HPV
Radiation therapy
T-cell repertoire

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging

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10.1016/j.brachy.2023.10.007

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Manzar, G. S., Alam, M. B. E., Lynn, E. J., Karpinets, T. V., Harris, T., Lo, D., Yoshida-Court, K., Napravnik, T. C., Sammouri, J., Lin, D., Andring, L. M., Bronk, J., Wu, X., Sims, T. T., Mathew, G., Schmeler, K. M., Eifel, P. J., Jhingran, A., Lin, L. L., ... Colbert, L. E. (2024). Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy. Brachytherapy, 23(2), 123-135. https://doi.org/10.1016/j.brachy.2023.10.007

Manzar, GS, Alam, MBE, Lynn, EJ, Karpinets, TV, Harris, T, Lo, D, Yoshida-Court, K, Napravnik, TC, Sammouri, J, Lin, D, Andring, LM, Bronk, J , Wu, X , Sims, TT, Mathew, G, Schmeler, KM, Eifel, PJ, Jhingran, A , Lin, LL , Joyner, MM, Zhang, J, Futreal, A , Klopp, AH & Colbert, LE 2024, 'Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy', Brachytherapy, vol. 23, no. 2, pp. 123-135. https://doi.org/10.1016/j.brachy.2023.10.007

@article{3f2a2b89c49041ee9a3b28e8d76cfe55,

title = "Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy",

abstract = "Background: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. Methods: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020–1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-β/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. Results: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2–50.2 fold-increase from baseline), frequency (1.2–1.7), rearrangements (1.2–40.2), and clonality (1.2–15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. Conclusion: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.",

keywords = "Antigen-specific immunity, Brachytherapy, Cervical cancer, HPV, Radiation therapy, T-cell repertoire",

author = "Manzar, {Gohar S.} and Alam, {Molly B.El} and Lynn, {Erica J.} and Karpinets, {Tatiana V.} and Timothy Harris and David Lo and Kyoko Yoshida-Court and Napravnik, {Tatiana Cisneros} and Julie Sammouri and Daniel Lin and Andring, {Lauren M.} and Julianna Bronk and Xiaogang Wu and Sims, {Travis T.} and Geena Mathew and Schmeler, {Kathleen M.} and Eifel, {Patricia J} and Anuja Jhingran and Lin, {Lilie L.} and Joyner, {Melissa M.} and Jianhua Zhang and Andrew Futreal and Klopp, {Ann H.} and Colbert, {Lauren E.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Brachytherapy Society",

year = "2024",

month = mar,

doi = "10.1016/j.brachy.2023.10.007",

language = "English (US)",

volume = "23",

pages = "123--135",

journal = "Brachytherapy",

issn = "1538-4721",

publisher = "Elsevier Inc.",

number = "2",

}

TY - JOUR

T1 - Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy

AU - Manzar, Gohar S.

AU - Alam, Molly B.El

AU - Lynn, Erica J.

AU - Karpinets, Tatiana V.

AU - Harris, Timothy

AU - Lo, David

AU - Yoshida-Court, Kyoko

AU - Napravnik, Tatiana Cisneros

AU - Sammouri, Julie

AU - Lin, Daniel

AU - Andring, Lauren M.

AU - Bronk, Julianna

AU - Wu, Xiaogang

AU - Sims, Travis T.

AU - Mathew, Geena

AU - Schmeler, Kathleen M.

AU - Eifel, Patricia J

AU - Jhingran, Anuja

AU - Lin, Lilie L.

AU - Joyner, Melissa M.

AU - Zhang, Jianhua

AU - Futreal, Andrew

AU - Klopp, Ann H.

AU - Colbert, Lauren E.

PY - 2024/3

Y1 - 2024/3

N2 - Background: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. Methods: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020–1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-β/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. Results: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2–50.2 fold-increase from baseline), frequency (1.2–1.7), rearrangements (1.2–40.2), and clonality (1.2–15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. Conclusion: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

AB - Background: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. Methods: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020–1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-β/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. Results: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2–50.2 fold-increase from baseline), frequency (1.2–1.7), rearrangements (1.2–40.2), and clonality (1.2–15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. Conclusion: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

KW - Antigen-specific immunity

KW - Brachytherapy

KW - Cervical cancer

KW - HPV

KW - Radiation therapy

KW - T-cell repertoire

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DO - 10.1016/j.brachy.2023.10.007

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AN - SCOPUS:85180948873

SN - 1538-4721

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ER -

Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy

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Keywords

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