01
Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells
Zhen Zhang, et al.
Nat Immunol. 2024
The mechanism of action of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy is not fully understood. They found that in patients with advanced melanoma, dual immune checkpoint inhibitor therapy with a combination of anti-PD-1 and anti-CTLA-4 showed better objective response rates and progression-free survival compared with anti-PD-1 monotherapy. PD-1+CD8+ T (TResp) cell populations in patients with advanced melanoma were analyzed by immunoassay, PD-1+CD8+ T cells under dual immune checkpoint inhibitor therapy showed enhanced cytotoxic capacity and increased granzyme B and perforin expression. At the same time, the cytokine expression profile was altered. Thus, the differential programming of TResp cells to combination therapy, from depletion to stronger cytotoxic effector programs, was determined. Anti-PD-1 monotherapy does not have this effect. Single-cell transcriptome and T cell receptor library analysis is used to identify effector programming alterations in expanded PD-1+CD8+ T cell clones with different regulatory uses, STAT1 and STAT3 utilization, and antitumor-specific combination and anti-CTLA-4 monotherapy associated with the interleukin (IL)-21 signaling pathway. In the B16F10 melanoma model with IL-21− deficiency or anti-IL-21 receptor blockade, the therapeutic effect of CTLA-4 blockade is lost. Taken together, these results show a critical role for IL-21 signaling in the efficacy of CTLA-4 checkpoint therapy. IL-21 is revealed to drive cytotoxic reprogramming of PD-1+CD8+ T cells via STAT1 or STAT3 signaling, either in combination with anti-PD-1 or in anti-CTLA-4 monotherapy.
DOI: 10.1038/s41590-024-02027-0
02
Huan Tong, et al.
Cell Metab. 2024
Colorectal cancer (CRC) is the third most common cancer worldwide, but treatment outcomes vary depending on the type of patient. In order to investigate the inhibitory effect of serine/glycine-free (-SG) diet on colorectal cancer and its regulatory mechanism on the tumor immune microenvironment, and to evaluate its potential therapeutic effect in combination with PD-1 inhibitors, they conducted animal experiments and clinical studies. First, mice were fed a serine/glycine-free (-SG) diet, and it was found that CRC tumorigenesis was inhibited, and a large number of T and B cells were induced, naïve T cells and effector T cells increased, and inhibitory regulatory T cells (Tregs) decreased. However, single-cell sequencing and experiments have found that tumors with -SG diet can lactate PD-L1, and have demonstrated that PD-L1 lactation can help delay PD-L1 degradation in tumors. The -SG diet activates hypoxia-inducible factor-1α (HIF-1α), enhances glycolysis and lactate production, thereby promoting PD-L1 lactation. Mutant PD-L1 lactation sites or knockdown of PD-L1 exhibit anti-tumor effects, suggesting that PD-L1 lactation is a negative regulatory mechanism. They achieved better anti-tumor efficacy with the combination of -SG diet and anti-PD-1 therapy in an animal model and demonstrated the safety of the -SG diet through a phase 1 clinical trial. In conclusion, the -SG diet not only inhibited tumor growth and promoted tumor cell death, but also enhanced T cell infiltration and cytotoxicity by altering the tumor microenvironment. In addition, the -SG diet also promotes tumor immune escape by increasing lactation of PD-L1.
DOI: 10.1016/j.cmet.2024.10.019
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