Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 Mar 2024
13 Mar 2024
Historique:
received:
29
03
2023
accepted:
06
03
2024
medline:
14
3
2024
pubmed:
14
3
2024
entrez:
14
3
2024
Statut:
epublish
Résumé
Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.
Identifiants
pubmed: 38480738
doi: 10.1038/s41467-024-46685-y
pii: 10.1038/s41467-024-46685-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2280Subventions
Organisme : Fondazione Italiana per la Ricerca sul Cancro (Italian Foundation for Cancer Research)
ID : IG 21635
Informations de copyright
© 2024. The Author(s).
Références
Brahmer, J. R. et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J. Immunother. Cancer 6, 75 (2018).
pubmed: 30012210
pmcid: 6048854
doi: 10.1186/s40425-018-0382-2
Remon, J. et al. Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations. J. Thorac. Oncol. 15, 914–947 (2020).
pubmed: 32179179
doi: 10.1016/j.jtho.2020.03.006
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
pubmed: 25765070
pmcid: 4993154
doi: 10.1126/science.aaa1348
Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).
pubmed: 30643254
pmcid: 6365097
doi: 10.1038/s41588-018-0312-8
Schoenfeld, A. J. & Hellmann, M. D. Acquired Resistance to Immune Checkpoint Inhibitors. Cancer Cell 37, 443–455 (2020).
pubmed: 32289269
pmcid: 7182070
doi: 10.1016/j.ccell.2020.03.017
Broz, M. L. et al. Dissecting the Tumor Myeloid Compartment Reveals Rare Activating Antigen-Presenting Cells Critical for T Cell Immunity. Cancer Cell 26, 938 (2014).
pubmed: 28898680
doi: 10.1016/j.ccell.2014.11.010
Diamond, M. S., Lin, J. H. & Vonderheide, R. H. Site-Dependent Immune Escape Due to Impaired Dendritic Cell Cross-Priming. Cancer Immunol. Res 9, 877–890 (2021).
pubmed: 34145076
pmcid: 8655819
doi: 10.1158/2326-6066.CIR-20-0785
Ghislat, G. et al. NF-kappaB-dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity. Sci. Immunol. 6, eabg3570 (2021).
pubmed: 34244313
doi: 10.1126/sciimmunol.abg3570
Sanchez-Paulete, A. R. et al. Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells. Cancer Discov. 6, 71–79 (2016).
pubmed: 26493961
doi: 10.1158/2159-8290.CD-15-0510
Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell 31, 711–723.e4 (2017).
pubmed: 28486109
pmcid: 5650691
doi: 10.1016/j.ccell.2017.04.003
Teijeira, A. et al. Depletion of Conventional Type-1 Dendritic Cells in Established Tumors Suppresses Immunotherapy Efficacy. Cancer Res. 82, 4373–4385 (2022).
pubmed: 36130020
doi: 10.1158/0008-5472.CAN-22-1046
Theisen, D. J. et al. WDFY4 is required for cross-presentation in response to viral and tumor antigens. Science 362, 694–699 (2018).
pubmed: 30409884
pmcid: 6655551
doi: 10.1126/science.aat5030
Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018).
pubmed: 29942093
pmcid: 6475503
doi: 10.1038/s41591-018-0085-8
Bottcher, J. P. et al. NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell 172, 1022–1037.e14 (2018).
pubmed: 29429633
pmcid: 5847168
doi: 10.1016/j.cell.2018.01.004
Garris, C. S. et al. Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-gamma and IL-12. Immunity 55, 1749 (2022).
pubmed: 36103861
doi: 10.1016/j.immuni.2022.07.021
MacNabb, B. W. et al. Dendritic cells can prime anti-tumor CD8(+) T cell responses through major histocompatibility complex cross-dressing. Immunity 55, 982–997.e8 (2022).
pubmed: 35617964
pmcid: 9883788
doi: 10.1016/j.immuni.2022.04.016
Caronni, N. et al. TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses. Nat. Commun. 12, 2237 (2021).
pubmed: 33854047
pmcid: 8046802
doi: 10.1038/s41467-021-22535-z
Caronni, N. et al. Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer. Cancer Res. 78, 1685–1699 (2018).
pubmed: 29363545
doi: 10.1158/0008-5472.CAN-17-1307
Horton, B. L. et al. Lack of CD8(+) T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer. Sci. Immunol. 6, eabi8800 (2021).
pubmed: 34714687
pmcid: 10786005
doi: 10.1126/sciimmunol.abi8800
Zagorulya, M. et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity 56, 386–405.e10 (2023).
pubmed: 36736322
pmcid: 10880816
doi: 10.1016/j.immuni.2023.01.010
Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).
pubmed: 32269339
pmcid: 7787191
doi: 10.1038/s41586-020-2134-y
Bhardwaj, N. et al. Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets. Nat. Cancer 1, 1204–1217 (2020).
pubmed: 35121932
doi: 10.1038/s43018-020-00143-y
Cueto, F. J. & Sancho, D. The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy. Cancers (Basel) 13, 1525 (2021).
pubmed: 33810248
doi: 10.3390/cancers13071525
Hegde, S. et al. Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer. Cancer Cell 37, 289–307.e9 (2020).
pubmed: 32183949
pmcid: 7181337
doi: 10.1016/j.ccell.2020.02.008
Oba, T. et al. Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s. Nat. Commun. 11, 5415 (2020).
pubmed: 33110069
pmcid: 7592056
doi: 10.1038/s41467-020-19192-z
Prokopi, A. et al. Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy. J. Immunother. Cancer 9, e000832 (2021).
pubmed: 33408092
pmcid: 7789456
doi: 10.1136/jitc-2020-000832
Salmon, H. et al. Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity 44, 924–938 (2016).
pubmed: 27096321
pmcid: 4980762
doi: 10.1016/j.immuni.2016.03.012
Svensson-Arvelund, J. et al. Expanding cross-presenting dendritic cells enhances oncolytic virotherapy and is critical for long-term anti-tumor immunity. Nat. Commun. 13, 7149 (2022).
pubmed: 36418317
pmcid: 9684150
doi: 10.1038/s41467-022-34791-8
Ho, W. W. et al. Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy. Proc. Natl. Acad. Sci. USA 118, e2105323118 (2021).
pubmed: 34725151
pmcid: 8609309
doi: 10.1073/pnas.2105323118
Ghasemi, A. et al. Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy. Nat. Cancer https://doi.org/10.1038/s43018-023-00668-y (2023).
Lai, J. et al. Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity. Nat. Immunol. 21, 914–926 (2020).
pubmed: 32424363
doi: 10.1038/s41590-020-0676-7
Martinez-Usatorre, A. et al. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci. Transl. Med 13, eabd1616 (2021).
pubmed: 34380768
pmcid: 7612153
doi: 10.1126/scitranslmed.abd1616
Gungabeesoon, J. et al. A neutrophil response linked to tumor control in immunotherapy. Cell 186, 1448–1464.e20 (2023).
pubmed: 37001504
doi: 10.1016/j.cell.2023.02.032
Schenkel, J. M. et al. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1(+) CD8(+) T cells in tumor-draining lymph nodes. Immunity 54, 2338–2353.e6 (2021).
pubmed: 34534439
pmcid: 8604155
doi: 10.1016/j.immuni.2021.08.026
Dimitrova, N. et al. Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development. Cancer Discov. 6, 188–201 (2016).
pubmed: 26586766
doi: 10.1158/2159-8290.CD-15-0854
Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017).
pubmed: 29186113
doi: 10.1038/nature24673
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
pubmed: 25838375
doi: 10.1126/science.aaa4971
Yamazaki, C. et al. Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. J. Immunol. 190, 6071–6082 (2013).
pubmed: 23670193
doi: 10.4049/jimmunol.1202798
Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF(high) neutrophils. Science 358, eaal5081 (2017).
pubmed: 29191879
pmcid: 6343476
doi: 10.1126/science.aal5081
Joo, H. G. et al. Expression and function of galectin-3, a beta-galactoside-binding protein in activated T lymphocytes. J. Leukoc. Biol. 69, 555–564 (2001).
pubmed: 11310841
doi: 10.1189/jlb.69.4.555
Takeda, Y., Azuma, M., Matsumoto, M. & Seya, T. Tumoricidal efficacy coincides with CD11c up-regulation in antigen-specific CD8(+) T cells during vaccine immunotherapy. J. Exp. Clin. Cancer Res. 35, 143 (2016).
pubmed: 27619885
pmcid: 5020536
doi: 10.1186/s13046-016-0416-x
Wang, X., Wang, J., Shen, H., Luo, Z. & Lu, X. Downregulation of TPX2 impairs the antitumor activity of CD8 + T cells in hepatocellular carcinoma. Cell Death Dis. 13, 223 (2022).
pubmed: 35273149
pmcid: 8913637
doi: 10.1038/s41419-022-04645-8
D’Alise, A. M. et al. Adenoviral-based vaccine promotes neoantigen-specific CD8(+) T cell stemness and tumor rejection. Sci. Transl. Med. 14, eabo7604 (2022).
pubmed: 35947675
pmcid: 9844517
doi: 10.1126/scitranslmed.abo7604
Siddiqui, I. et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity 50, 195–211.e10 (2019).
pubmed: 30635237
doi: 10.1016/j.immuni.2018.12.021
Cabeza-Cabrerizo, M. et al. Tissue clonality of dendritic cell subsets and emergency DCpoiesis revealed by multicolor fate mapping of DC progenitors. Sci. Immunol. 4, eaaw1941 (2019).
pubmed: 30824528
pmcid: 6420147
doi: 10.1126/sciimmunol.aaw1941
Helft, J. et al. Cross-presenting CD103+ dendritic cells are protected from influenza virus infection. J. Clin. Invest. 122, 4037–4047 (2012).
pubmed: 23041628
pmcid: 3484433
doi: 10.1172/JCI60659
Bougneres, L. et al. A role for lipid bodies in the cross-presentation of phagocytosed antigens by MHC class I in dendritic cells. Immunity 31, 232–244 (2009).
pubmed: 19699172
pmcid: 2803012
doi: 10.1016/j.immuni.2009.06.022
Du, X. et al. Hippo/Mst signalling couples metabolic state and immune function of CD8alpha(+) dendritic cells. Nature 558, 141–145 (2018).
pubmed: 29849151
pmcid: 6292204
doi: 10.1038/s41586-018-0177-0
de Mingo Pulido, A. et al. TIM-3 Regulates CD103(+) Dendritic Cell Function and Response to Chemotherapy in Breast Cancer. Cancer Cell 33, 60–74.e6 (2018).
pubmed: 29316433
pmcid: 5764109
doi: 10.1016/j.ccell.2017.11.019
Hellmann, M. D. et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N. Engl. J. Med. 378, 2093–2104 (2018).
pubmed: 29658845
pmcid: 7193684
doi: 10.1056/NEJMoa1801946
Lo, J. A. et al. Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses. Sci. Transl. Med. 13, eabd8636 (2021).
pubmed: 33597266
pmcid: 8130008
doi: 10.1126/scitranslmed.abd8636
Nguyen, K. B. et al. Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression. Elife 12, e85263 (2023).
pubmed: 37548358
pmcid: 10425174
doi: 10.7554/eLife.85263
Fessenden, T. B. et al. Dendritic cell-mediated cross presentation of tumor-derived peptides is biased against plasma membrane proteins. J. Immunother. Cancer 10, e004159 (2022).
pubmed: 35820727
pmcid: 9277371
doi: 10.1136/jitc-2021-004159
Peng, Q. et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat. Commun. 11, 4835 (2020).
pubmed: 32973173
pmcid: 7518441
doi: 10.1038/s41467-020-18570-x
Lussier, D. M. et al. Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads. Proc. Natl Acad. Sci. USA. 118, e2102611118 (2021).
pubmed: 34099555
pmcid: 8214694
doi: 10.1073/pnas.2102611118
Ho, W. W., Pittet, M. J., Fukumura, D. & Jain, R. K. The local microenvironment matters in preclinical basic and translational studies of cancer immunology and immunotherapy. Cancer Cell 40, 701–702 (2022).
pubmed: 35714604
pmcid: 10894502
doi: 10.1016/j.ccell.2022.05.016
Lavin, Y. et al. Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-. Cell Anal. Cell 169, 750–765.e17 (2017).
Gueguen, P. et al. Contribution of resident and circulating precursors to tumor-infiltrating CD8(+) T cell populations in lung cancer. Sci. Immunol. 6, eabd5778 (2021).
pubmed: 33514641
doi: 10.1126/sciimmunol.abd5778
van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8(+) T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20, 218–232 (2020).
pubmed: 32024970
pmcid: 7115982
doi: 10.1038/s41568-019-0235-4
Ferris, S. T. et al. cDC1 prime and are licensed by CD4(+) T cells to induce anti-tumour immunity. Nature 584, 624–629 (2020).
pubmed: 32788723
pmcid: 7469755
doi: 10.1038/s41586-020-2611-3
Tay, R. E., Richardson, E. K. & Toh, H. C. Revisiting the role of CD4(+) T cells in cancer immunotherapy-new insights into old paradigms. Cancer Gene Ther. 28, 5–17 (2021).
pubmed: 32457487
doi: 10.1038/s41417-020-0183-x
Wculek, S. K. et al. Effective cancer immunotherapy by natural mouse conventional type-1 dendritic cells bearing dead tumor antigen. J. Immunother. Cancer 7, 100 (2019).
pubmed: 30961656
pmcid: 6454603
doi: 10.1186/s40425-019-0565-5
Lin, D. S. et al. Single-cell analyses reveal the clonal and molecular aetiology of Flt3L-induced emergency dendritic cell development. Nat. Cell Biol. 23, 219–231 (2021).
pubmed: 33649477
doi: 10.1038/s41556-021-00636-7
Corti, G. et al. A Genomic Analysis Workflow for Colorectal Cancer Precision Oncology. Clin. Colorectal Cancer 18, 91–101.e3 (2019).
pubmed: 30981604
doi: 10.1016/j.clcc.2019.02.008
Rospo, G. et al. Evolving neoantigen profiles in colorectal cancers with DNA repair defects. Genome Med. 11, 42 (2019).
pubmed: 31253177
pmcid: 6599263
doi: 10.1186/s13073-019-0654-6
Wang, K. et al. MapSplice: accurate mapping of RNA-seq reads for splice junction discovery. Nucleic Acids Res. 38, e178 (2010).
pubmed: 20802226
pmcid: 2952873
doi: 10.1093/nar/gkq622
Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinforma. 12, 323 (2011).
doi: 10.1186/1471-2105-12-323
Zheng, G. X. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).
pubmed: 28091601
pmcid: 5241818
doi: 10.1038/ncomms14049
Germain, P. L., Lun, A., Garcia Meixide, C., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using scDblFinder. F1000Res 10, 979 (2021).
pubmed: 35814628
doi: 10.12688/f1000research.73600.1
Haghverdi, L., Lun, A. T. L., Morgan, M. D. & Marioni, J. C. Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. Nat. Biotechnol. 36, 421–427 (2018).
pubmed: 29608177
pmcid: 6152897
doi: 10.1038/nbt.4091
Zhao, J. et al. Detection of differentially abundant cell subpopulations in scRNA-seq data. Proc. Natl Acad. Sci. USA 118, e2100293118 (2021).
pubmed: 34001664
pmcid: 8179149
doi: 10.1073/pnas.2100293118
Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).
pubmed: 31740819
pmcid: 6884693
doi: 10.1038/s41592-019-0619-0
Becht, E. et al. Dimensionality reduction for visualizing single-cell data using UMAP. Nat Biotechnol. https://doi.org/10.1038/nbt.4314 (2018).