Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

Kumagai S ，Koyama S ，Itahashi K ，Tanegashima T ，Lin YT ，Togashi Y ，Kamada T ，Irie T ，Okumura G ，Kono H ，Ito D ，Fujii R ，Watanabe S ，Sai A ，Fukuoka S ，Sugiyama E ，Watanabe G ，Owari T ，Nishinakamura H ，Sugiyama D ，Maeda Y ，Kawazoe A ，Yukami H ，Chida K ，Ohara Y ，Yoshida T ，Shinno Y ，Takeyasu Y ，Shirasawa M ，Nakama K ，Aokage K ，Suzuki J ，Ishii G ，Kuwata T ，Sakamoto N ，Kawazu M ，Ueno T ，Mori T ，Yamazaki N ，Tsuboi M ，Yatabe Y ，Kinoshita T ，Doi T ，Shitara K ，Mano H ，Nishikawa H ... -  《-》

The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies.

Kumagai S ，Togashi Y ，Kamada T ，Sugiyama E ，Nishinakamura H ，Takeuchi Y ，Vitaly K ，Itahashi K ，Maeda Y ，Matsui S ，Shibahara T ，Yamashita Y ，Irie T ，Tsuge A ，Fukuoka S ，Kawazoe A ，Udagawa H ，Kirita K ，Aokage K ，Ishii G ，Kuwata T ，Nakama K ，Kawazu M ，Ueno T ，Yamazaki N ，Goto K ，Tsuboi M ，Mano H ，Doi T ，Shitara K ，Nishikawa H ... -  《-》

Remodeling of the tumor microenvironment via disrupting Blimp1(+) effector Treg activity augments response to anti-PD-1 blockade.

Accumulation of Foxp3+ regulatory T (Treg) cells in the tumor often represents an important mechanism for cancer immune evasion and a critical barrier to anti-tumor immunity and immunotherapy. Many tumor-infiltrating Treg cells display an activated phenotype and express the transcription factor Blimp1. However, the specific impact of these Blimp1+ Treg cells and their follicular regulatory T (TFR) cell subset on tumor and the underlying mechanisms of action are not yet well-explored. Various transplantable tumor models were established in immunocompetent wild-type mice and mice with a Foxp3-specific ablation of Blimp1. Tumor specimens from patients with metastatic melanoma and TCGA datasets were analyzed to support the potential role of Treg and TFR cells in tumor immunity. In vitro culture assays and in vivo adoptive transfer assays were used to understand how Treg, TFR cells and antibody responses influence tumor control. RNA sequencing and NanoString analysis were performed to reveal the transcriptome of tumor-infiltrating Treg cells and tumor cells, respectively. Finally, the therapeutic effects of anti-PD-1 treatment combined with the disruption of Blimp1+ Treg activity were evaluated. Blimp1+ Treg and TFR cells were enriched in the tumors, and higher tumoral TFR signatures indicated increased risk of melanoma metastasis. Deletion of Blimp1 in Treg cells resulted in impaired suppressive activity and a reprogramming into effector T-cells, which were largely restricted to the tumor-infiltrating Treg population. This destabilization combined with increased anti-tumor effector cellular responses, follicular helper T-cell expansion, enhanced tumoral IgE deposition and activation of macrophages secondary to dysregulated TFR cells, remodeled the tumor microenvironment and delayed tumor growth. The increased tumor immunogenicity with MHC upregulation improved response to anti-PD-1 blockade. Mechanistically, Blimp1 enforced intratumoral Treg cells with a unique transcriptional program dependent on Eomesodermin (Eomes) expression; deletion of Eomes in Blimp1-deficient Treg cells restored tumor growth and attenuated anti-tumor immunity. These findings revealed Blimp1 as a new critical regulator of tumor-infiltrating Treg cells and a potential target for modulating Treg activity to treat cancer. Our study has also revealed two FCERIA-containing immune signatures as promising diagnostic or prognostic markers for melanoma patients.

Dixon ML ，Luo L ，Ghosh S ，Grimes JM ，Leavenworth JD ，Leavenworth JW ... -  《Molecular Cancer》

Tumor microenvironment dictates regulatory T cell phenotype: Upregulated immune checkpoints reinforce suppressive function.

Kim HR ，Park HJ ，Son J ，Lee JG ，Chung KY ，Cho NH ，Shim HS ，Park S ，Kim G ，In Yoon H ，Kim HG ，Jung YW ，Cho BC ，Park SY ，Rha SY ，Ha SJ ... -  《Journal for ImmunoTherapy of Cancer》

Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma.

Less than 20% of melanoma patients respond to programmed cell death-1 (PD-1) blockade immunotherapies. Thus, it is crucial to understand the dynamic changes in the tumor microenvironment (TME) after PD-1 blockade, for developing immunotherapy efficacy. A genomic analysis was conducted by The Cancer Genome Atlas (TCGA) datasets and web platform TIMER2.0 datasets. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells, and B16-F10 melanoma mice were used as models. The cellular and molecular characteristics and mechanisms of Treg cells in melanoma were assessed by performing gene expression studies, immunohistochemistry, RNA sequencing, and flow cytometry. Here, we evaluate the countenance of T cell immunoglobulin and mucin-domain containing-3 (Tim-3), and various immunosuppressive factors within tumor-infiltrated Treg cells after treatment with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. Increased expression of Tim-3 is markedly observed within the tissues of the PD-1 blockade resistance of melanoma patients. Targeting STAT3 significantly boosts the response of resistant-PD-1 therapy within the melanoma mouse model. Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual PBMCs and the murine melanoma model, limiting the immunosuppression of Treg cells. Our findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.

Huang L ，Xu Y ，Fang J ，Liu W ，Chen J ，Liu Z ，Xu Q ... -  《Frontiers in Immunology》