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 ca...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/4/e006392.full |
| _version_ | 1827963787508973568 |
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| author | Paul K Wallace Thomas Schwaab Scott I Abrams Elizabeth A Repasky Alexis Conway Jason B Muhitch Jacky Chow Adil Khan Madeline Gaudieri Brianna J Wasik Kah Teong Soh Anurag K Singh |
| author_facet | Paul K Wallace Thomas Schwaab Scott I Abrams Elizabeth A Repasky Alexis Conway Jason B Muhitch Jacky Chow Adil Khan Madeline Gaudieri Brianna J Wasik Kah Teong Soh Anurag K Singh |
| author_sort | Paul K Wallace |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-09T17:04:35Z |
| format | Article |
| id | doaj.art-be083ad959af46eea3224d5aecd46e1e |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-09T17:04:35Z |
| publishDate | 2023-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-be083ad959af46eea3224d5aecd46e1e2023-04-20T19:30:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-04-0111410.1136/jitc-2022-006392Tumor and immune remodeling following radiotherapy in human renal cell carcinomaPaul K Wallace0Thomas Schwaab1Scott I Abrams2Elizabeth A Repasky3Alexis Conway4Jason B Muhitch5Jacky Chow6Adil Khan7Madeline Gaudieri8Brianna J Wasik9Kah Teong Soh10Anurag K Singh113Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USAAff1 Department of UrologyRoswell Park Comprehensive Cancer Center Buffalo New York USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USAFlow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Flow and Image Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USADepartment of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USABackground 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.https://jitc.bmj.com/content/11/4/e006392.full |
| spellingShingle | Paul K Wallace Thomas Schwaab Scott I Abrams Elizabeth A Repasky Alexis Conway Jason B Muhitch Jacky Chow Adil Khan Madeline Gaudieri Brianna J Wasik Kah Teong Soh Anurag K Singh Tumor and immune remodeling following radiotherapy in human renal cell carcinoma Journal for ImmunoTherapy of Cancer |
| 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 |
| url | https://jitc.bmj.com/content/11/4/e006392.full |
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