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Translational Theraputics

Harnessing tumor immunity with cytotoxics: T cells monitoring in mice bearing lung tumors treated with anti-VEGF and pemetrexed-cisplatin doublet

British Journal of Cancer volume 129, pages 1373–1382 (2023)Cite this article

Abstract

Background

Successful immunotherapy is restricted to some cancers only, and combinatorial strategies with other drugs could help to improve their efficacy. Here, we monitor T cells in NSCLC model after treatment with cytotoxics (CT) and anti-VEGF drugs, to understand when immune checkpoint inhibitors should be best associated next.

Methods

In vivo study was performed on BALB/c mice grafted with KLN205 cells. Eight treatments were tested including control, cisplatin and pemetrexed as low (LD CT) and full (MTD CT) dose as single agents, flat dose anti-VEGF and the association anti-VEGF + CT. Full immunomonitoring was performed by flow cytometry on tumor, spleen and blood over 3 weeks.

Results

Immunomodulatory effect was dependent upon both treatments and time. In tumors, combination groups shown numerical lower Treg cells on Day 21. In spleen, anti-VEGF and LD CT group shown higher CD8/Treg ratio on Day 7; on Day 14, higher T CD4 were observed in both combination groups. Finally, in blood, Tregs were lower and CD8/Treg ratio higher, on Day 14 in both combination groups. On Day 21, CD4 and CD8 T cells were higher in the anti-VEGF + MTD CT group.

Conclusions

Anti-VEGF associated to CT triggers notable increase in CD8/Tregs ratio. Regarding the scheduling, a two-week delay after using anti-VEGF and CT could be the best sequence to optimize antitumor efficacy.

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Fig. 1: Summary of dosing and sampling for blood, spleen and tumors.
Fig. 2: FACS quantitation of CDA4, CD8 and Treg lymphocytes in tumor depending on treatment.
Fig. 3: FACS quantitation of CDA4, CD8 and Treg lymphocytes in spleen depending on treatment.
Fig. 4
Fig. 5: FACS quantitation of CDA4, CD8 and Treg lymphocytes in blood depending on treatment.
Fig. 6

Data availability

Raw data and details regarding the different analysis will be made available upon reasonable request to the Corresponding author.

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Funding

Funding

This work was supported by Amidex Foundation-initiative d’Excellence and the Aix-Marseille Université.

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Authors and Affiliations

  1. SMARTc & COMPO Team, CRCM Inserm U1068, Aix Marseille University, 13007, Marseille, France

    G. Sicard, D. Protzenko, S. Giacometti, J. Ciccolini & R. Fanciullino

  2. School of Medicine, Aix Marseille University, 13007, Marseille, France

    F. Barlési

  3. Gustave Roussy Institute, 94800, Villejuif, France

    F. Barlési

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  1. G. Sicard
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Contributions

GS, DP, SG, FB, RF, and JC performed the bench experiments. GS, DP, and JC performed statistical analyses. GS, RF and JC wrote the manuscript. All authors contributed toward data analysis, drafting and revising the paper, and agree to be accountable for all aspects of the work.

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Correspondence to J. Ciccolini.

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Sicard, G., Protzenko, D., Giacometti, S. et al. Harnessing tumor immunity with cytotoxics: T cells monitoring in mice bearing lung tumors treated with anti-VEGF and pemetrexed-cisplatin doublet. Br J Cancer 129, 1373–1382 (2023). https://doi.org/10.1038/s41416-023-02350-7

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