A recentBritish Journal of Cancerstudy investigated how cancer stem cells (CSCs) induce resistance to chimeric antigen receptor T (CAR-T) cell therapy. Furthermore, the effect of Interleukin-24 (IL-24) on CSCs and CAR-T cell therapy was evaluated.

Study:IL-24 improves efficacy of CAR-T cell therapy by targeting stemness of tumor cells. Image Credit:Juan Gaertner/Shutterstock.com

CSCs are a sub-population of cancer cells that exhibit similar characteristic features to normal stem cells or progenitor cells. These cells, also known as tumor-initiating cells, contribute to tumor onset, recurrence, progression, and metastasis.

Previous studies indicated that CSCs are a major contributor to treatment resistance. It has been difficult to eliminate CSCs because of the changes in their signaling pathways.

CAR-T cell therapy has displayed significant efficacy in the treatment of hematological malignancies. However, this therapy was found to be less effective for the treatment of solid tumors.

Several strategies, such as chemokine receptors, cytokines, metabolic reprogramming, and costimulatory signals, have been developed to improve the therapeutic outcome against solid tumors.

Some studies have demonstrated the contribution of IL-7, chemokine ligand 19 (CCL19),and C-X-C chemokine receptor type 5(CXC-R5) in improving therapeutic efficacy for treating solid tumors.

For instance, CXCR5 use has positively enhanced immune cell infiltration and CAR-T cell survival in tumor lesions.

CAR-T cell therapy often targets mucin 1 (MUC1), a transmembrane protein of the mucin family. Previous studies have shown that IL-22 upregulates the expression of MUC1 for CAR-T cell therapy.

Therefore, metabolic engineering can substantially improve the therapeutic activity of CART cells via enhancement in cell proliferation and infiltration.

A key drawback of this technique is that it mainly focuses on tumor microenvironment and T cells and completely ignores CSCs.

Typically, the expression of IL24 is downregulated in tumors. It is important to note that IL-24 is involved with the induction of apoptosis of tumor cells through multiple pathways, such as DNA damage, serotonin antagonist and reuptake inhibitors (SARIs), apoptosis-inducing factor (AIF), and the beclin-1 axis.

IL-24 augments the chemotherapeutic and antibody-mediated cell therapies by eliminating both unsorted cancer cells and enriched CSCs.

Although the antitumor activity of IL-24 has been documented, its efficacy in tumor immunotherapy is not fully understood.

In vitroandin vivoexperiments were conducted to determine the effect of CSCs on CAR-T cell therapy. IL-24-expressing CAR-T cells were generated to improve the efficacy of engineered T cells to eliminate CSCs.

Tumor cells targeted by CAR-T cells require the expression of antigens. NKG2DLs and Her2 are the two most frequent tumor antigens used as targets in CAR-T therapy to treat esophageal and lung cancers.

A lactic dehydrogenase (LDH) release assay was performed to evaluate the cytolytic capacities of CAR-T cells. Significant antigen-dependent cytolytic capability was observed when compared with control T cells.

Furthermore, elevated IL-2 and IFN- were synthesized by CAR-T cells in a dose-dependent and antigen-specific manner.

The finding of this study highlighted the capacity of the engineered CAR-T cells to eliminate antigen-positive tumor cells. Even though the CAR-T cells efficiently killed most tumor cells, residual tumor cells existed.

To better understand the tumor cell resistance to CAR-T cells, residual tumor cells were collected after being treated with trypsin for digestion.

Experimental results indicated that the targeted antigen expressions were not changed by CAR-T cell therapy. Furthermore, mRNA levels remained unchanged post-CAR-T cell therapy.

qRT-PCR analysis revealed an elevated expression of CSC markers. Tumor-forming experiments using NOD-SCID mice revealed residual tumor cells had a strong tumor-forming capacity.

These results indicate that CSCs are resistant to CAR-T cell therapy. Therefore, it is imperative to completely clear CSCs to improve the antitumor activity of CAR-T cells.

Considering the capacity of IL-24 to induce apoptosis and inhibit stemness of tumor cells, the current study assessed the effectiveness of IL-24 in reducing CSC resistance for CAR-T cell therapy.

It was observed that low-level expression of IL-24 in lung and esophageal cancer tissues was associated with poor disease outcomes.

In line with previous research findings, this study documented the antitumor activity of IL-24. A recombinant IL-24 protein was added to the tumor cells to understand the effect of IL-24 on tumor viability.

Bioluminescence imaging (BLI) assays were conducted, which revealed that tumor cell viability was significantly affected by IL-24.

The experimental findings indicated that IL-24 treatment inhibits -catenin activation and enhances caspase-3 activation. Furthermore, a reduction in the tumorigenic ability of CSCs was observed post IL-24 treatment.

In vitroandin vivoexperimental findings indicate that IL-24 induces CSC apoptosis and reduces the stemness of tumor cells. IL-24 expression was strongly correlated with higher T-cell infiltration in lung and esophageal cancer tissues.

Taken together, this study highlighted the potential of IL-24 in elevating T-cell activation, proliferation, and central memory differentiation, which augments the efficacy of CAR-T cell therapy.

At present, phase I clinical trials are being conducted to evaluate the efficacy of IL-24-expressing CAR-T cell therapy to treat solid tumors.

Journal reference:

Zhang, K., Hu, W., Li, F., Wen, C., Zhou, L., Zhang, L., Lian, J., Liu, S., Wang, S., & Zhang, Y. (2024). IL-24 improves efficacy of CAR-T cell therapy by targeting stemness of tumor cells. British Journal of Cancer. pp.1-11. doi:https://doi.org/10.1038/s41416-024-02601-1

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