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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