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

• Type of Material: Article
• Authors: Zachary Buchwald, Emory University; Tahseen H. Nasti, Emory University; Judong Lee, Emory University; Christiane S. Eberhardt, Emory University; Andreas Wieland, Emory University; Sejin Im, Emory University; David Lawson, Emory University; Walter Curran Jr, Emory University; Rafi Ahmed, Emory University; Mohammad Khan, Emory University
• Language: English
• Date: 2020-01-01
• Publisher: BMJ PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © Author(s) (or their employer(s)) 2020.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/jitc-2020-000867
• Title of Journal or Parent Work: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• Volume: 8
• Issue: 2
• Grant/Funding Information: Cristian Badea: Mouse micro-CT imaging was performed at the Duke Center for In Vivo Microscopy, an NIH/NIBIB national Biomedical Technology Resource Center (P41 EB015897), and was also supported by the NIH National Cancer Institute (R01 CA196667, U24 CA220245).; ZSB: ASCO Young Investigator Award; RA: NIH NIAID R01; MKK: American Cancer Society- Institutional Research Grant; Seed Grant from the Melanoma Research Fund of Winship Cancer Institute.
• Keywords: radiotherapy; CD8-Positive T-Lymphocytes; IMMUNITY; Oncology; Immunology; Life Sciences & Biomedicine; ACTIVATION; PERSISTENCE; CANCER; MELANOMA; DISSECTION; immunity; cellular; METASTASIS; lymphocytes; adaptive immunity; EXPRESSION; Science & Technology; CD8 T-CELLS; THERAPY; tumor-infiltrating
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

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.