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A novel agonist of 4-1BB costimulatory receptor shows therapeutic efficacy against a tobacco carcinogen-induced lung cancer

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Abstract

Immunotherapy utilizing checkpoint inhibitors has shown remarkable success in the treatment of cancers. In addition to immune checkpoint inhibitors, immune co-stimulation has the potential to enhance immune activation and destabilize the immunosuppressive tumor microenvironment. CD137, also known as 4-1BB, is one of the potent immune costimulatory receptors that could be targeted for effective immune co-stimulation. The interaction of the 4-1BB receptor with its natural ligand (4-1BBL) generates a strong costimulatory signal for T cell proliferation and survival. 4-1BBL lacks costimulatory activity in soluble form. To obtain co-stimulatory activity in soluble form, a recombinant 4-1BBL protein was generated by fusing the extracellular domains of murine 4-1BBL to a modified version of streptavidin (SA-4-1BBL). Treatment with SA-4-1BBL inhibited the development of lung tumors in A/J mice induced by weekly injections of the tobacco carcinogen NNK for eight weeks. The inhibition was dependent on the presence of T cells and NK cells; depletion of these cells diminished the SA-4-1BBL antitumor protective effect. The number of lung tumor nodules was significantly reduced by the administration of SA-4-1BBL to mice during ongoing exposure to NNK. The data presented in this paper suggest that utilizing an immune checkpoint stimulator as a single agent generate a protective immune response against lung cancer in the presence of a carcinogen. More broadly, this study suggests that immune checkpoint stimulation can be extended to a number of other cancer types, including breast and prostate cancers, for which improved diagnostics can detect disease at the preneoplastic stage.

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Data availability

SA-4-1BBL protein is available through a material transfer agreement with the University of Missouri, Columbia, MO.

Abbreviations

H&E:

Hematoxylin and eosin

IHC:

Immunohistochemical staining

NNK:

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

PCNA:

Proliferating cell nuclear antigen

DMSO:

Dimethyl sulfide

SA:

Streptavidin

s.c.:

Subcutaneous injection

i.p.:

Intraperitoneal injection

PD-1:

Programmed cell death protein-1

PD-L1:

Programmed death-ligand 1

IFNγ:

Interferon γ

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Acknowledgements

The authors thank The NextGen Precision Health Building, at the University of Missouri-Columbia for providing advanced core facilities. The authors also thank Dr. Christa Jackson for her critical reading of the manuscript

Funding

This study was supported by the Department of Defense (DoD) grant number LC190524.

Author information

Author notes

  1. Rakesh Rudraboina and Mohammad Tarique have contributed equally to this work.

  2. Haval Shirwan and Esma S. Yolcu have share senior authorship.

Authors and Affiliations

  1. Department of Child Health, University of Missouri, Columbia, MO, USA

    Ayse Ece Gulen, Rakesh Rudraboina, Mohammad Tarique, Vahap Ulker, Haval Shirwan & Esma S. Yolcu

  2. Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA

    Haval Shirwan & Esma S. Yolcu

  3. NextGen Precision Health, University of Missouri, Columbia, MO, USA

    Ayse Ece Gulen, Rakesh Rudraboina, Mohammad Tarique, Vahap Ulker, Haval Shirwan & Esma S. Yolcu

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  1. Ayse Ece Gulen
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Contributions

Conception and design were done by ESY and HS. AEG, RR, MT and VU performed the experiments. AEG, RR and MT analyzed data and prepared Figs. 1, 2, 3 and 4. ESY, HS and AEG wrote the manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Haval Shirwan or Esma S. Yolcu.

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Conflict of interest

H.S. is CEO of Fascure Therapeutics, LLC, and the Scientific Co-Founder, stockholder, and member of SAB for iTolerance, Inc. E.S.Y. is a consultant for iTolerance. The remaining authors declare no conflict of interest.

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Gulen, A.E., Rudraboina, R., Tarique, M. et al. A novel agonist of 4-1BB costimulatory receptor shows therapeutic efficacy against a tobacco carcinogen-induced lung cancer. Cancer Immunol Immunother 72, 3567–3579 (2023). https://doi.org/10.1007/s00262-023-03507-2

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