Deficiency of metabolic regulator PKM2 activates the pentose phosphate
pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy![]()
Markowitz, G.J., et al.
TCF1+ progenitor-exhausted
CD8+ T cells share key similarities with memory cells and mediate
more durable antitumor immunity than their TCF1- effector-like
counterparts. Upon antigenic stimulation, CD8+ T cells
differentiate, with marked alterations in the transcriptional and metabolic landscape,
with effector cells upregulating aerobic glycolysis to support their
proliferative and cytotoxic phenotypes. Recent studies have assessed the
potential of manipulating metabolic pathways, but it remains poorly understood
how transcriptional and metabolic reprogramming affects CD8+ T cell
differentiation and impacts antitumor efficacy. Here, researchers showed that targeting
glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in
elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a
TCF1high progenitor-exhausted-like phenotype and increased
responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T
cells showed reduced glycolytic flux, accumulation of glycolytic intermediates
and PPP metabolites and increased PPP cycling as determined by 1,2-13C
glucose carbon tracing. Small molecule agonism of the PPP without acute
glycolytic impairment skewed CD8+ T cells toward a TCF1highpopulation, generated a unique transcriptional landscape and adoptive transfer
of agonist-treated CD8+ T cells enhanced tumor control in mice in
combination with PD-1 blockade and promoted tumor killing in patient-derived
tumor organoids. This study demonstrates a new metabolic reprogramming that
contributes to a progenitor-like T cell state to promote immunotherapy
efficacy.
DOI: 10.1038/s41590-024-01963-1
Cutting Edge: LAG3 Dimerization Is Required
for TCR/CD3 Interaction and Inhibition of Antitumor Immunity![]()
Kieran Adam, et al.
LAG3 is an inhibitory receptor that
plays a critical role in controlling T cell tolerance and autoimmunity and is a
major immunotherapeutic target. The early studies examining the biochemical
requirements for LAG3 function showed that LAG3 exists as a dimer on the cell
surface. The crystal structures for both human LAG3 and murine LAG3 (mLAG3)
resolved as dimers, mediated by several residues within the D2 domain producing
a highly hydrophobic region. Specifically, Trp (W180), Phe (F214 and F219), and
Leu (L182 and L221) residues create a hydrophobic pocket that is analogous to
human LAG3 (W184, F225, F227, and I186). So here the authors propose the hypothesis
that dimerization is required for LAG3 function. In this study, they showed
that the association between the TCR/CD3 complex and a murine LAG3 mutant that
cannot dimerize is perturbed in CD8+ T cells. Their results also showed that
LAG3 dimerization is required for optimal inhibitory function in a B16-gp100
tumor model. They further demonstrated that a therapeutic LAG3 Ab, C9B7W, which
does not block LAG3 interaction with its cognate ligand MHC class II, disrupts
LAG3 dimerization and its association with the TCR/CD3 complex. These results
highlight the functional importance of LAG3 dimerization and offer additional
approaches to therapeutically target LAG3.
DOI: 10.4049/jimmunol.2300673
Editor & Reviewer: Shiyang Song
