| Autor: |
Bruno L. Cadilha, Stefan Endres, Hannah Obeck, K Manske, Matthias Seifert, Sebastian Kobold, Duc Huynh, F Märkl, Klara Dorman, A Öner, Benmebarek, T Lorenzini, S Stoiber |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Oral Presentations. |
| DOI: |
10.1136/jitc-2021-itoc8.1 |
| Popis: |
Background CAR T cell therapy remains ineffective in solid tumors. Scarce T cell infiltration and T cell suppression at the tumor site are two notable therapy limitations. T regulatory (Treg) cells are capable of suppressing effective anti-tumor responses through inhibitory factors such as transforming growth factor β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been found to accumulate and to correlate with poor prognosis in breast cancer. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. Materials and Methods CCR8 and DNR can be expressed in murine and human T cells upon retroviral transduction. T cell receptor (TCR) and chimeric antigen receptor (CAR) antigen specific models in murine and human systems were utilized. qPCR, IF microscopy, ELISA and the cancer genome atlas (TCGA) database were used in the steps of ligand identification and hypothesis generation. We employed flow cytometry and multi-photon intra-vital microscopy to interrogate infiltration, proliferation and phenotype of T cell products. Mechanistically, CRISPR was used to dissect the role of the CCL1-CCR8 positive feedback loop in T cell therapy. Results We identified that in an in vivo pancreatic murine model of cancer, the CCR8 gene was upregulated in tumor infiltrated lymphocytes compared to T cells that accumulated in the spleen. In this same tumor model, CCL1 could be detected in tumor explants. We identified that this secreted CCL1 from activated effector T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. The introduction of CCR8 and DNR receptors in primary T cells improved migration towards CCL1 and improved proliferation capacity in the presence of TGF-β. Besides these effects, these receptors did not further impact effector and memory phenotype or secretome of T cell products. The CCR8-driven sustained and improved infiltration synergized with TGF-β-shielding conferred by the DNR for improved therapeutic efficacy, allowing tumor rejection in models that are otherwise completely resistant to CAR T cell therapy. Conclusions We conclude that the combination of CCR8- and DNR-transduction into antigen-specific T cells can exploit two critical biological axes to render T cell therapy effective in solid tumors such as pancreatic cancer. Beyond TGF-β, relieving other immunosuppressive axes may further sustain a CCL1 feedback loop mechanism to improve anti-tumoral function of CCR8+ ACT. This therapeutic approach could be extended to other Treg-rich solid tumor entities where limited infiltration into the tumor and intra-tumoral T cell proliferation prevent therapeutic success. Furthermore, the CCL1-CCR8 axis heralds the potential to be used as a target to improve the efficacy of immunotherapies beyond ACT. Disclosure Information B.L. Cadilha: None. M.R. Benmebarek: None. K. Dorman: None. A. Oner: None. T. Lorenzini: None. H. Obeck: None. S. Stoiber: None. D. Huynh: None. F. Markl: None. M. Seifert: None. K. Manske: None. S. Endres: None. S. Kobold: None. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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