Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Author’s View
  • Published:

Next-generation DC vaccines with an immunogenic trajectory against cancer: therapeutic opportunities vs. resistance mechanisms

Genes & Immunity (2024)Cite this article

Dendritic cells (DCs) have attracted considerable attention as potential targets for the development of therapeutic cancer vaccines. This approach generally involves the differentiation of DCs from autologous, patient-derived monocytes, followed by ex vivo DC exposure to an appropriate source of tumour associated antigens (TAAs) or neoantigens in the context of immunostimulatory maturation cocktails, and culminating with the reinfusion of these stimulated DCs back into the patient [1, 2]. Accumulating clinical evidence demonstrates that this approach often promotes some degree of TAA/neoantigen-specific T cell driven immunity in patients [3, 4]. However, the success of such therapeutic regimens in the clinic has been inconsistent, raising an acute need for innovation in this field. This is especially relevant for tumours that display an immunosuppressive phenotype, distinguished by low T cell infiltration but high myeloid content, since these are almost completely resistant to all the current immunotherapies [5, 6]. Although the field of therapeutic DC vaccination has made vast progress through a plethora of preclinical and clinical research, DC vaccines still need to move towards a ‘next-generation’ that is clinically useful [7, 8]. Currently, there are at least three areas in which the development of next-generation DC vaccines is progressing: (1) utilization of specific DC subsets [9], (2) the source of antigen entailing either personalized neoantigens or more immunogenic forms of cancer cell death to allow more effective antigen “pulsing” of DCs, and (3) the stimulatory factors used for activating DCs [10, 11]. Besides, for DC vaccines to succeed in the future, it is important to understand the exact immunological resistance pathway limiting its efficacy. The latter area has received less attention than the former three. Moreover, the gaps between preclinical and clinical settings from the angle of cross-species translational immunology have been seldom addressed.

Next, we wanted to understand the in vivo mechanism of action as well as possible mechanisms behind the failure of a DCvax-IT formulation. Hence, we created a preclinical version of DCvax-IT using a combination of immunogenic cancer cell death (ICD) with IFNβ that faithfully recapitulated the clinical immunogenic DC trajectory in terms of an upregulated antigen presentation, type I IFN response and pro-inflammatory immuno-cytokine profile. Indeed, this DCvax-IT favoured type I IFN responses over macrophage-like and mreg DC-like phenotypes. In vivo, DCvax-IT showed a high capacity at inducing preventive anticancer immunity but failed to induce a curative immunity against murine immunosuppressive tumours. This, despite the observations that, DCvax-IT was successfully reaching the lymph node (LN). This hinted at a potential (hitherto unknown) resistance mechanism that might be limiting T cell activation following anticancer vaccination.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Schematic overview of the design of DCvax-IT and the discovery of the PD-L1+ macrophage-based immunoresistance pathway.

References

  1. Laureano RS, Sprooten J, Vanmeerbeerk I, Borras DM, Govaerts J, Naulaerts S, et al. Trial watch: Dendritic cell (DC)-based immunotherapy for cancer. Oncoimmunology. 2022;11:2096363. https://doi.org/10.1080/2162402X.2022.2096363.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Najafi S, Mortezaee K. Advances in dendritic cell vaccination therapy of cancer. Biomed Pharmacother. 2023;164:114954. https://doi.org/10.1016/j.biopha.2023.114954.

    Article  CAS  PubMed  Google Scholar 

  3. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15:e257–67. https://doi.org/10.1016/S1470-2045(13)70585-0.

    Article  CAS  PubMed  Google Scholar 

  4. Lin MJ, Svensson-Arvelund J, Lubitz GS, Marabelle A, Melero I, Brown BD, et al. Cancer vaccines: the next immunotherapy frontier. Nat Cancer. 2022;3:911–26. https://doi.org/10.1038/s43018-022-00418-6.

    Article  CAS  PubMed  Google Scholar 

  5. Naulaerts S, Datsi A, Borras DM, Antoranz Martinez A, Messiaen J, Vanmeerbeek I, et al. Multiomics and spatial mapping characterizes human CD8+T cell states in cancer. Sci Transl Med. 2023;15:eadd1016. https://doi.org/10.1126/scitranslmed.add1016.

    Article  CAS  PubMed  Google Scholar 

  6. Borràs DM, Verbandt S, Ausserhofer M, Sturm G, Lim J, Verge GA, et al. Single cell dynamics of tumor specificity vs bystander activity in CD8+T cells define the diverse immune landscapes in colorectal cancer. Cell Discov. 2023;9:114. https://doi.org/10.1038/s41421-023-00605-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fan T, Zhang M, Yang J, Zhu Z, Cao W, Dong C. Therapeutic cancer vaccines: advancements, challenges, and prospects. Signal Transduct Target Ther. 2023;8:450. https://doi.org/10.1038/s41392-023-01674-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fu C, Ma T, Zhou L, Mi Q-S, Jiang A. Dendritic Cell-Based Vaccines Against Cancer: Challenges, Advances and Future Opportunities. Immunol Invest. 2022;51:2133–58. https://doi.org/10.1080/08820139.2022.2109486.

    Article  CAS  PubMed  Google Scholar 

  9. Chen MY, Zhang F, Goedegebuure SP, Gillanders WE. Dendritic cell subsets and implications for cancer immunotherapy. Front Immunol. 2024;15:1393451. https://doi.org/10.3389/fimmu.2024.1393451.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mahaki H, Ravari H, Kazemzadeh G, Lotfian E, Daddost RA, Avan A, et al. Pro-inflammatory responses after peptide-based cancer immunotherapy. Heliyon. 2024;10:e32249. https://doi.org/10.1016/j.heliyon.2024.e32249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fujioka Y, Ueki H, A Ruhan, Sasajima A, Tomono T, Ukawa M, et al. The Improved Antigen Uptake and Presentation of Dendritic Cells Using Cell-Penetrating D-octaarginine-Linked PNVA-co-AA as a Novel Dendritic Cell-Based Vaccine. Int J Mol Sci. 2024;25:5997. https://doi.org/10.3390/ijms25115997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sprooten J, Vanmeerbeek I, Datsi A, Govaerts J, Naulaerts S, Laureano RS, et al. Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+T cells. Cell Rep Med. 2024;5:101377. https://doi.org/10.1016/j.xcrm.2023.101377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kinget L, Naulaerts S, Govaerts J, Vanmeerbeek I, Sprooten J, Laureano RS, et al. A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma. Nat Med. 2024;30:1667–79. https://doi.org/10.1038/s41591-024-02978-9.

    Article  CAS  PubMed  Google Scholar 

  14. Vanmeerbeek I, Naulaerts S, Sprooten J, Laureano RS, Govaerts J, Trotta R, et al. Targeting conserved TIM3+VISTA+ tumor-associated macrophages overcomes resistance to cancer immunotherapy. Sci Adv. 2024;10:eadm8660. https://doi.org/10.1126/sciadv.adm8660.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Laureano RS, Vanmeerbeek I, Sprooten J, Govaerts J, Naulaerts S, Garg AD. The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy. Immunol Rev. 2024;321:71–93. https://doi.org/10.1111/imr.13287.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

ADG is supported by Research Foundation Flanders (FWO) (Fundamental Research Grant, G0B4620N; Excellence of Science/EOS grant, 30837538, for ‘DECODE’ consortium; Strategic Basic Research or SBO grant, S000523N), KU Leuven (C1 grant, C14/24/122; and C3 grants, C3/23/067, C3/21/037, C3/22/022), Come Up Against Cancer or Kom op Tegen Kanker (KOTK/2018/11509/1 and KOTK/2019/11955/1), VLIR-UOS (iBOF grant, iBOF/21/048, for ‘MIMICRY’ consortium), Olivia Hendrickx Research Foundation (OHRF), and European Union (EU) Mission Cancer grant for the GLIOMATCH consortium (Project no. 101136670). JS was funded by Kom op tegen Kanker (Stand up to Cancer), the Flemish cancer society through the Emmanuel van der Schueren (EvDS) PhD fellowship (projectID: 12699) and KU Leuven's Postdoctoral Mandate (PDM) fellowship.

Author information

Authors and Affiliations

  1. Department of Cellular & Molecular Medicine, Laboratory of Cell Stress & Immunity, KU Leuven, Leuven, Belgium

    Jenny Sprooten & Abhishek D. Garg

Authors
  1. Jenny Sprooten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abhishek D. Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abhishek D. Garg.

Ethics declarations

Competing interests

ADG received consulting/advisory/lecture honoraria or R&D contracts from Boehringer Ingelheim (Germany), Miltenyi Biotec (Germany), Novigenix (Switzerland), Sotio (Czech Republic) and IsoPlexis (USA). The other authors have no conflicts of interest to declare.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sprooten, J., Garg, A.D. Next-generation DC vaccines with an immunogenic trajectory against cancer: therapeutic opportunities vs. resistance mechanisms. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00294-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/s41435-024-00294-3

Search

Advanced search

Quick links