Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells

Neoadjuvant Immunotherapy in Gastroesophageal Cancer: A Promising Early Signal?

“…[48][49][50] The picture may be more complex, since PD-1 function may differ depending on the developmental stage of Tregs and the tissue environment. 51,52 Our best approach in current clinical practice for elucidating the therapeutic target-that is, monoplexed quantification of PD-L1 expression on tumor cells and indiscriminately on unspecified immune cells (aka CPS)-does not adequately tease this apart. Multiplexed analysis, facilitated by spatial and single-cell evaluation, can quantify the target according to distinct cell types and may help elucidate these potentially opposing effects.…”

Targets of tumor microenvironment for potential drug development

“…A recent study showed that blockade or ablation of PD-1 can enhance antitumor immunity by destabilizing Treg cell lineage and metabolic fitness in TME, and selectively deleting PD-1 in Treg cells has been shown to impede tumor progression, suggesting a potential therapeutic avenue in cancer treatment. 44 Pilato and colleagues' study revealed that disrupting the CARMA1-BCL10-MALT1 signalosome complex in tumor-infiltrating CD4 + Treg cells leads to a significant production of interferon γ (IFNγ), resulting in the suppression of tumor growth. Importantly, the genetic deletion of CARMA1 in a subset of Treg cells, carefully balanced to prevent systemic autoimmunity, was shown to be sufficient for eliciting this antitumor effect.…”

“…Nevertheless, the role of PD‐1 in tumor‐infiltrating Treg cells remains debatable. A recent study showed that blockade or ablation of PD‐1 can enhance antitumor immunity by destabilizing Treg cell lineage and metabolic fitness in TME, and selectively deleting PD‐1 in Treg cells has been shown to impede tumor progression, suggesting a potential therapeutic avenue in cancer treatment 44 . Pilato and colleagues' study revealed that disrupting the CARMA1–BCL10–MALT1 signalosome complex in tumor‐infiltrating CD4 + Treg cells leads to a significant production of interferon γ (IFNγ), resulting in the suppression of tumor growth.…”

Decoding the crosstalk between mevalonate metabolism and T cell function

“…Loss of SCAP was associated with reduced PD-1 expression and increased IFNγ secretion, both of which have known roles in destabilizing intratumoral T regs . 212,213 It was proposed that decreased PD1 in SCAP-deficient T regs results from disrupted prenylation of RAC; however, the localization of RAC and its downstream signaling was not directly assessed. Mevalonate synthesis and protein geranylgeranylation are absolutely required for normal development of T regs at steady state.…”

“…These data reveal that regulation by SREBP is context‐dependent, even within the same cell type. Loss of SCAP was associated with reduced PD‐1 expression and increased IFNγ secretion, both of which have known roles in destabilizing intratumoral T regs 212,213 . It was proposed that decreased PD1 in SCAP‐deficient T regs results from disrupted prenylation of RAC; however, the localization of RAC and its downstream signaling was not directly assessed.…”