Immunotherapy with Glutamine to Treat Cancer (SJ-23-0010)

St. Jude Reference #SJ-23-0010

Description

Cancer cells evade T cell-mediated killing through tumour–immune interactions whose mechanisms are not well understood. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumors.

Researchers at St. Jude found that intratumoral glutamine supplementation not only reduces tumor growth, but also overcomes the resistance to immune checkpoint blockade immunotherapies, which depend on cDC1 and lymphocytes. Intratumoral glutamine supplementation also significantly enhances the efficacy of adoptive T cell transfer therapies. Compared with previous approaches of glutamine metabolism inhibitors that mostly target tumor cells, glutamine supplementation may reduce the toxicity induced by these drugs. The efficacy of DC vaccines may also be improved by targeting glutamine pathway or downstream lysosomal signaling to treat cancers or boost the efficacy of immunotherapies.

Moreover, genetic depletion of glutamine transporter SLC38A2 in tumor cells significantly reduces tumor growth, and increased glutamine availability in tumor microenvironment that may overcome tumor-induced immunosuppression and enhance the efficacy of DC vaccination. Also, glutamine signals through lysosomal signaling to maintain cDC1 function, so targeting lysosomal signaling in DCs enhanced the efficacy of anti-PD-1 immune checkpoint blockade or other immunotherapies, indicating that targeting lysosomal signaling in DCs can be harnessed to achieve more efficient cancer therapies.

Altogether, their findings establish glutamine-mediated intercellular metabolic crosstalk between tumor cells and cDC1 that underpins tumor immunoevasion, and reveal glutamine acquisition and signaling in cDC1 as limiting events and non-canonical signals for DC functions and putative targets for cancer treatment such as:

• Glutamine supplementation combined with immune checkpoint blockade therapy (e.g. anti-PD-1/PD-L1 treatment) to enhance the efficacy of immunotherapies.
• DC vaccines for cancer treatments by targeting lysosomal signaling.
• Combination of lysosomal targeting-based DC vaccination with immune checkpoint blockade therapy.
• Targeting of SLC38A2 for tumor therapy.

Keywords

Intratumoral glutamine supplementation, tumor growth, resistance to immune checkpoint blockade immunotherapies, cDC1, lymphocytes, glutamine metabolism inhibitors, lysosomal signaling, cancers, immunotherapies, glutamine-mediated intercellular metabolic crosstalk, checkpoint blockade therapy, anti-PD-1/PD-L1, DC vaccine, SLC38A2

Granted patents or published applications

Unpublished application pending.

Related scientific references

Guo, C., You, Z., Shi, H. et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature 620, 200–208 (2023). https://doi.org/10.1038/s41586-023-06299-8

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