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Tumor and immune remodeling following radiotherapy in human renal cell carcinoma
BACKGROUND: Studies evaluating peripheral patient samples show radiation can modulate immune responses, yet the biological changes in human tumors particularly at the cellular level remain largely unknown. Here, we address how radiation treatment shapes the immune compartment and interactions with c...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124322/ https://www.ncbi.nlm.nih.gov/pubmed/37080610 http://dx.doi.org/10.1136/jitc-2022-006392 |
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author | Chow, Jacky Khan, Adil Gaudieri, Madeline Wasik, Brianna J Conway, Alexis Soh, Kah Teong Repasky, Elizabeth A Schwaab, Thomas Wallace, Paul K Abrams, Scott I Singh, Anurag K Muhitch, Jason B |
author_facet | Chow, Jacky Khan, Adil Gaudieri, Madeline Wasik, Brianna J Conway, Alexis Soh, Kah Teong Repasky, Elizabeth A Schwaab, Thomas Wallace, Paul K Abrams, Scott I Singh, Anurag K Muhitch, Jason B |
author_sort | Chow, Jacky |
collection | PubMed |
description | BACKGROUND: Studies evaluating peripheral patient samples show radiation can modulate immune responses, yet the biological changes in human tumors particularly at the cellular level remain largely unknown. Here, we address how radiation treatment shapes the immune compartment and interactions with cancer cells within renal cell carcinoma (RCC) patient tumors. METHODS: To identify how radiation shaped the immune compartment and potential immune interactions with tumor cells we evaluated RCC tumors from patients treated only with nephrectomy or with radiation followed by nephrectomy. Spectral flow cytometry using a 35-marker panel was performed on cell suspensions to evaluate protein expression within immune subsets. To reveal how radiation alters programming of immune populations and interactions with tumor cells, we examined transcriptional changes by single-cell RNA sequencing (scRNAseq). RESULTS: Spectral flow cytometry analysis revealed increased levels of early-activated as well as effector programmed cell death protein-1 (PD-1)(+) CD8 T-cell subsets within irradiated tumors. Following quality control, scRNAseq of tumor samples from nephrectomy-only or radiation followed by nephrectomy-treated patients generated an atlas containing 34,626 total cells. Transcriptional analysis revealed increased transition from stem-like T-cell populations to effector T cells in irradiated tumors. Interferon (IFN) pathways, that are central to radiation-induced immunogenicity, were enriched in irradiated lymphoid, myeloid, and cancer cell populations. Focused cancer cell analysis showed enhanced antigen presentation and increased predicted TRAIL-mediated and IFN-mediated interactions between tumor cells and the same effector T-cell subsets increased by radiation. TRAIL and IFN pathways enriched in irradiated tumors were associated with survival in patients treated with immunotherapy. CONCLUSIONS: These findings identify the source of IFN enrichment within irradiated RCC and reveal heightened levels of PD-1(+) CD8(+) T-cell subsets and increased probability of interactions with tumor cells following standalone radiation treatment. This study provides a window into the irradiated tumor-immune microenvironment of patients and rationale for treatment combinations. |
format | Online Article Text |
id | pubmed-10124322 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-101243222023-04-25 Tumor and immune remodeling following radiotherapy in human renal cell carcinoma Chow, Jacky Khan, Adil Gaudieri, Madeline Wasik, Brianna J Conway, Alexis Soh, Kah Teong Repasky, Elizabeth A Schwaab, Thomas Wallace, Paul K Abrams, Scott I Singh, Anurag K Muhitch, Jason B J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Studies evaluating peripheral patient samples show radiation can modulate immune responses, yet the biological changes in human tumors particularly at the cellular level remain largely unknown. Here, we address how radiation treatment shapes the immune compartment and interactions with cancer cells within renal cell carcinoma (RCC) patient tumors. METHODS: To identify how radiation shaped the immune compartment and potential immune interactions with tumor cells we evaluated RCC tumors from patients treated only with nephrectomy or with radiation followed by nephrectomy. Spectral flow cytometry using a 35-marker panel was performed on cell suspensions to evaluate protein expression within immune subsets. To reveal how radiation alters programming of immune populations and interactions with tumor cells, we examined transcriptional changes by single-cell RNA sequencing (scRNAseq). RESULTS: Spectral flow cytometry analysis revealed increased levels of early-activated as well as effector programmed cell death protein-1 (PD-1)(+) CD8 T-cell subsets within irradiated tumors. Following quality control, scRNAseq of tumor samples from nephrectomy-only or radiation followed by nephrectomy-treated patients generated an atlas containing 34,626 total cells. Transcriptional analysis revealed increased transition from stem-like T-cell populations to effector T cells in irradiated tumors. Interferon (IFN) pathways, that are central to radiation-induced immunogenicity, were enriched in irradiated lymphoid, myeloid, and cancer cell populations. Focused cancer cell analysis showed enhanced antigen presentation and increased predicted TRAIL-mediated and IFN-mediated interactions between tumor cells and the same effector T-cell subsets increased by radiation. TRAIL and IFN pathways enriched in irradiated tumors were associated with survival in patients treated with immunotherapy. CONCLUSIONS: These findings identify the source of IFN enrichment within irradiated RCC and reveal heightened levels of PD-1(+) CD8(+) T-cell subsets and increased probability of interactions with tumor cells following standalone radiation treatment. This study provides a window into the irradiated tumor-immune microenvironment of patients and rationale for treatment combinations. BMJ Publishing Group 2023-04-19 /pmc/articles/PMC10124322/ /pubmed/37080610 http://dx.doi.org/10.1136/jitc-2022-006392 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Clinical/Translational Cancer Immunotherapy Chow, Jacky Khan, Adil Gaudieri, Madeline Wasik, Brianna J Conway, Alexis Soh, Kah Teong Repasky, Elizabeth A Schwaab, Thomas Wallace, Paul K Abrams, Scott I Singh, Anurag K Muhitch, Jason B Tumor and immune remodeling following radiotherapy in human renal cell carcinoma |
title | Tumor and immune remodeling following radiotherapy in human renal cell carcinoma |
title_full | Tumor and immune remodeling following radiotherapy in human renal cell carcinoma |
title_fullStr | Tumor and immune remodeling following radiotherapy in human renal cell carcinoma |
title_full_unstemmed | Tumor and immune remodeling following radiotherapy in human renal cell carcinoma |
title_short | Tumor and immune remodeling following radiotherapy in human renal cell carcinoma |
title_sort | tumor and immune remodeling following radiotherapy in human renal cell carcinoma |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124322/ https://www.ncbi.nlm.nih.gov/pubmed/37080610 http://dx.doi.org/10.1136/jitc-2022-006392 |
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