Tumor cell–derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8 ⁺ T cell activation

Abstract

The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8 + T cell–dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.

Blood leukocytes as a non-invasive diagnostic tool for thyroid nodules: a prospective cohort study

“…These receptors are responsible for recognizing foreign antigens and triggering immune signal transduction pathways. Blood leukocytes also play a significant role in inflammation response and immune cell activation [ 103 – 105 ]. Methylation can influence the expression of immune-related genes in leukocytes, including antigen-presenting genes, immune checkpoint genes, and effector molecules of cytotoxic T cells, with profound implications for immune evasion, and immune suppression [ 106 , 107 ].…”

Metabolic instruction of the graft-versus-leukemia immunity

“…(C) The polyamine spermidine produced by leukemic cells boosts the differentiation of CD4 + T cells into T regs ( 124 ). Additionally, spermidine might negatively influence the CD8 + T cell proliferation and function ( 125 ). (D) Mutant IDH1/2 converts the TCA cycle intermediate α-ketoglutarate into the oncometabolite R-2-HG ( 92 , 93 ).…”

“…The higher concentrations of polyamines might affect the activity of CD8 + T cells; however, it is not yet clear in which direction as studies concerning AML and allo-HCT specifically have not been published. While some reports suggest that spermidine suppresses T cell function ( 125 , 143 , 144 , 147 ), others indicate that spermidine can enhance T cell function ( 148 , 149 ). One study demonstrated, for example, that the addition of spermidine suppressed the proliferation of CD8 + T cells activated with anti-CD3 and anti-CD28 antibodies in vitro as well as in vivo .…”

“…The treatment of B16F10 tumor-bearing mice with the polyamine synthesis inhibitor eflornithine reduced tumor growth and enhanced CD8 + T cell infiltration. The combination of eflornithine with an anti-PD-1 antibody further potentiated anti-tumor immunity ( 125 ). In contrast, spermidine supplementation was shown to improve the anti-tumor activity of PD-L1 antibody treatment in a MC38 colon cancer model.…”

Investigating chimeric antigen receptor T cell therapy and the potential for cancer immunotherapy (Review)

“…Immunotherapy encompasses strategies aimed at overcoming immune suppression by blocking inhibitory receptors such as CTLA-4 and PD-1 (immune checkpoint inhibitors) and stimulating antitumor immune responses through adoptive transfer T cell therapy ( 13-15 ). The introduction of checkpoint inhibitors, such as ipilimumab targeting CTLA-4, has revolutionized the field and shown promising results.…”