Overcoming Metabolic T-Cell Suppression in Cancer Immunotherapy using metabolic engineering

Cancer immunotherapy has become well established as a promising approach to cancer treatment and cure. CAR-T therapy showed high response rates for hematologic cancer patients. However, the clinical results of those treatments for solid cancers are quite poor.

One of the major limitations of solid tumor immunotherapies is metabolic suppression of the immune cells in the tumor microenvironment (TME). Cancer cells require metabolic reprogramming to supply their energetic needs for rapid growth, which leads to low metabolite availability in the TME and T cell suppression.

We suggest a novel approach for overcoming metabolic deprivation in the TME, by overexpression of metabolic enzyme-coding genes in the T cells. We established a unique in vivo screening method for identifying metabolic genes with high potential for T cell function enhancement.

The screening method includes a pooled transduction of a metabolic ORF library into T cells, followed by an Adoptive cell transfer (ACT) to tumor-bearing mice with the pooled modified T cells. A Few days after the ACT, we extract DNA from the tumor and conduct a semi-quantitative sequencing by NGS. The most abundant genes in the analysis are those that gave the cells an advantage in terms of penetration to the tumor, proliferation, or survival. The selected genes from the screening will be tested individually both in vivo and in vitro for T cell activity examination.

The presented method for overcoming T cell suppression in the TME can dramatically improve T cell function and significantly advance immunotherapy treatments.