Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins
Background For effective tumor elimination, cytotoxic CD8+ T cells must recognize tumor-derived antigens presented on class I major histocompatibility complex (MHC-I). Despite a general association between the expression of immunogenic antigens, typically neoantigens, and response to immunotherapy,...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/7/e004159.full |
| _version_ | 1811224443897249792 |
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| author | Stefani Spranger Fiona Chatterjee Esmee P Hoefsmit Tim B Fessenden Lauren E Stopfer Julian Zulueta Josh Mesfin Therese Cordero Dumit Irene Reijers Christian Blank Forest White |
| author_facet | Stefani Spranger Fiona Chatterjee Esmee P Hoefsmit Tim B Fessenden Lauren E Stopfer Julian Zulueta Josh Mesfin Therese Cordero Dumit Irene Reijers Christian Blank Forest White |
| author_sort | Stefani Spranger |
| collection | DOAJ |
| description | Background For effective tumor elimination, cytotoxic CD8+ T cells must recognize tumor-derived antigens presented on class I major histocompatibility complex (MHC-I). Despite a general association between the expression of immunogenic antigens, typically neoantigens, and response to immunotherapy, the majority of patients lack strong endogenous responses to most putative neoantigens due to mechanisms that are not well understood. Cytotoxic CD8+ T-cell responses are induced by dendritic cells (DCs) cross-presenting tumor-derived peptides on MHC-I. We hypothesized that cross presentation may form an unappreciated source of bias in the induction of cytotoxic T-cell responses.Methods We used stable isotope labeling of amino acids combined with immunopeptidomics to distinguish cross-presented from endogenous MHC-I peptides on DCs. To test impacts on T-cell activation, we targeted the model antigen SIINFEKL to specific subcellular compartments in tumor cells, which were used as sources for cross presentation to T cells. In vitro observations were validated using DNA and RNA sequencing data from two cohorts of patients with melanoma undergoing checkpoint blockade therapy. We used a novel quantitative mass spectrometry approach to measure the levels of model antigen on cross-presenting DCs following various means of tumor cell death.Results DCs exhibited a strong bias for cross-presenting peptides derived from cytoplasmic proteins and against those from plasma membrane proteins, which was confirmed using the model antigen SIINFEKL. In patients with melanoma, the proportion of membrane-derived neoantigens was correlated with reduced survival and failure to respond to therapy. Quantification of cross-presented SIINFEKL revealed that the mode of cell death could overcome DCs’ bias against plasma membrane proteins.Conclusions Cross presentation of cellular antigens by DCs may impose constraints on the range of peptides available to activate CD8+ T cells that have previously gone unappreciated. The share of neoantigens arising from membrane-derived sources may render some tumors less immunogenic due to inefficient cross presentation. These observations carry important implications for the encounter and intracellular processing of cellular antigens by DCs and merit further clinical studies for their therapeutic potential in stratifying patient populations and design of vaccine-based therapies.Sorry this seems to be the only funciton that works yes I confirm TBF, LES and FC are joint first authors. Please that away the line TFB and FC contributed equally. thanks!! |
| first_indexed | 2024-04-12T08:49:16Z |
| format | Article |
| id | doaj.art-6e47349a08334a24aaee85b7133f5532 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-12T08:49:16Z |
| publishDate | 2022-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-6e47349a08334a24aaee85b7133f55322022-12-22T03:39:37ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-07-0110710.1136/jitc-2021-004159Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteinsStefani Spranger0Fiona Chatterjee1Esmee P Hoefsmit2Tim B Fessenden3Lauren E Stopfer4Julian Zulueta5Josh Mesfin6Therese Cordero Dumit7Irene Reijers8Christian Blank9Forest White10Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USARadiology, Royal London Hospital, London, UKMolecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The NetherlandsKoch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USAKoch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USAKoch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USADepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USAKoch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USADepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsKoch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USABackground For effective tumor elimination, cytotoxic CD8+ T cells must recognize tumor-derived antigens presented on class I major histocompatibility complex (MHC-I). Despite a general association between the expression of immunogenic antigens, typically neoantigens, and response to immunotherapy, the majority of patients lack strong endogenous responses to most putative neoantigens due to mechanisms that are not well understood. Cytotoxic CD8+ T-cell responses are induced by dendritic cells (DCs) cross-presenting tumor-derived peptides on MHC-I. We hypothesized that cross presentation may form an unappreciated source of bias in the induction of cytotoxic T-cell responses.Methods We used stable isotope labeling of amino acids combined with immunopeptidomics to distinguish cross-presented from endogenous MHC-I peptides on DCs. To test impacts on T-cell activation, we targeted the model antigen SIINFEKL to specific subcellular compartments in tumor cells, which were used as sources for cross presentation to T cells. In vitro observations were validated using DNA and RNA sequencing data from two cohorts of patients with melanoma undergoing checkpoint blockade therapy. We used a novel quantitative mass spectrometry approach to measure the levels of model antigen on cross-presenting DCs following various means of tumor cell death.Results DCs exhibited a strong bias for cross-presenting peptides derived from cytoplasmic proteins and against those from plasma membrane proteins, which was confirmed using the model antigen SIINFEKL. In patients with melanoma, the proportion of membrane-derived neoantigens was correlated with reduced survival and failure to respond to therapy. Quantification of cross-presented SIINFEKL revealed that the mode of cell death could overcome DCs’ bias against plasma membrane proteins.Conclusions Cross presentation of cellular antigens by DCs may impose constraints on the range of peptides available to activate CD8+ T cells that have previously gone unappreciated. The share of neoantigens arising from membrane-derived sources may render some tumors less immunogenic due to inefficient cross presentation. These observations carry important implications for the encounter and intracellular processing of cellular antigens by DCs and merit further clinical studies for their therapeutic potential in stratifying patient populations and design of vaccine-based therapies.Sorry this seems to be the only funciton that works yes I confirm TBF, LES and FC are joint first authors. Please that away the line TFB and FC contributed equally. thanks!!https://jitc.bmj.com/content/10/7/e004159.full |
| spellingShingle | Stefani Spranger Fiona Chatterjee Esmee P Hoefsmit Tim B Fessenden Lauren E Stopfer Julian Zulueta Josh Mesfin Therese Cordero Dumit Irene Reijers Christian Blank Forest White Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins Journal for ImmunoTherapy of Cancer |
| title | Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins |
| title_full | Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins |
| title_fullStr | Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins |
| title_full_unstemmed | Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins |
| title_short | Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins |
| title_sort | dendritic cell mediated cross presentation of tumor derived peptides is biased against plasma membrane proteins |
| url | https://jitc.bmj.com/content/10/7/e004159.full |
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