Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy

Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programm...

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Autores principales:	David Lawson, Zachary S Buchwald, Tahseen H Nasti, Judong Lee, Christiane S Eberhardt, Se Jin Im, Walter Curran, Rafi Ahmed, Mohammad K Khan, Andreas Wieland
Formato:	article
Lenguaje:	EN
Publicado:	BMJ Publishing Group 2020
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/7c7d8658ae3d4abb9d68605872b992f4
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spelling	oai:doaj.org-article:7c7d8658ae3d4abb9d68605872b992f42021-12-04T18:00:05ZTumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy10.1136/jitc-2020-0008672051-1426https://doaj.org/article/7c7d8658ae3d4abb9d68605872b992f42020-10-01T00:00:00Zhttps://jitc.bmj.com/content/8/2/e000867.fullhttps://doaj.org/toc/2051-1426Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response.Methods We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells.Results We show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8+ T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8+ T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8+ T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8+ and stem-like CD8+ T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8+ T-cells and stem-like CD8+ T-cells in both the irradiated and unirradiated tumor.Conclusions These correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8+ T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.David LawsonZachary S BuchwaldTahseen H NastiJudong LeeChristiane S EberhardtSe Jin ImWalter CurranRafi AhmedMohammad K KhanAndreas WielandBMJ Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal for ImmunoTherapy of Cancer, Vol 8, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 David Lawson Zachary S Buchwald Tahseen H Nasti Judong Lee Christiane S Eberhardt Se Jin Im Walter Curran Rafi Ahmed Mohammad K Khan Andreas Wieland Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
description	Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response.Methods We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells.Results We show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8+ T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8+ T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8+ T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8+ and stem-like CD8+ T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8+ T-cells and stem-like CD8+ T-cells in both the irradiated and unirradiated tumor.Conclusions These correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8+ T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.
format	article
author	David Lawson Zachary S Buchwald Tahseen H Nasti Judong Lee Christiane S Eberhardt Se Jin Im Walter Curran Rafi Ahmed Mohammad K Khan Andreas Wieland
author_facet	David Lawson Zachary S Buchwald Tahseen H Nasti Judong Lee Christiane S Eberhardt Se Jin Im Walter Curran Rafi Ahmed Mohammad K Khan Andreas Wieland
author_sort	David Lawson
title	Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
title_short	Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
title_full	Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
title_fullStr	Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
title_full_unstemmed	Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
title_sort	tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy
publisher	BMJ Publishing Group
publishDate	2020
url	https://doaj.org/article/7c7d8658ae3d4abb9d68605872b992f4
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Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy

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