Program DHC-Virtual
20 - 21 January 2021
Abstracts Immunology session 2
The CCL4-CCR5 axis promotes local T-cell migration of cellular immunotherapy in leukemia
20 January
12:06 12:18
A. Meringa

The CCL4-CCR5 axis promotes local T-cell migration of gamma delta TCR based immunotherapy in the leukemic bone marrow niche.

Angelo Meringa (1), Zsolt Sebestyen (1), Jurgen Kuball (1)
(1) UMC Utrecht, Center of Translational Immunology , Utrecht
No potential conflicts of interest

T-cell based therapies such and CAR T-cells and alpha/beta TCR clones have shown promising results in clinical trials for the treatment of hematological malignancies. However, both T-cell therapies required expression of tumor specific molecules presented on the tumor cell surface. Furthermore, CAR T-cells show a lack of active, non-exhausted T-cells at the tumor site leading to reduced efficacy and tumor escape. Gamma delta TCR based therapies can be an interesting alternative since this TCR does not induce tumor escape by sensing metabolic changes within the tumor cell instead of an antigen. In order to gain more insight in the infiltration behavior and exhaustion of these T cells, an 3D in vitro model of the leukemic bone marrow niche was used to follow the T-cells in the TME.



mesenchymal stem cells (MSCs) and endothelial cells (EC) are known to play a important role in the tumor microenvironment (TME) of leukemia. Therefore, MSCs and endothelial progenitor cells were seeded together with a range of leukemia's in Matrigel and co-cultured for 4 days. After this, gamma delta TCR transduced alpha/beta T-cells (TEGs) were administered and assessed on targeting different leukemia's.



Luminex analysis of the supernatant from these 3D models show an increased secretion of a range of chemokine and cytokines upon administration of tumor-reactive TEG cells. Receptors for these upregulated cytokines were also found to be overexpressed on the TEG cells upon administration. Blocking these chemokines, and in the case of CCL4 the receptor as well, reduced T-cell infiltration and thereby the tumor killing capacity was observed.



Our results suggest that the CCL4-CCR5 axis is an important axis in the chemokine-dependent attraction of tumor reactive TEGs towards the tumor in the bone marrow TME. This axis and potential other chemokine axis such as CXCL1-.... can be used to boost T-cell infiltration in both hematological and possibly non-hematological malignancies by overexpressing certain chemokine receptors. Furthermore, this phenomenon could also be used to boost efficacy of other T-cell based therapies such as CAR T-cells