Editors' ChoiceCancer

Improving metabolic fitness of antitumor immune cells

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Science Translational Medicine  17 Jun 2020:
Vol. 12, Issue 548, eabc8947
DOI: 10.1126/scitranslmed.abc8947

Abstract

CD8+ T cells accumulate lipids that drive metabolic dysfunction in tumors.

CD8+ T cells are major effectors of antitumor immunity but often acquire an exhausted phenotype that fails to control tumor growth. The therapeutic results of immunotherapy that aims to reactivate antitumor T cells through immune checkpoint blockade have been heterogeneous, especially in solid tumors like pancreatic ductal adenocarcinoma. Better knowledge of the mechanisms that regulate the function and persistence of infiltrating CD8+ T cells within the immunosuppressive tumor microenvironment may therefore pave the way to efficient immunotherapy. Because immune cell activation is supported and regulated by intracellular metabolic changes, Manzo et al. aimed to define the metabolic features of CD8+ T cells within the microenvironment of solid pancreatic ductal adenocarcinoma (PDAC) tumors.

First, they applied imaging mass spectrometry to reveal that tumor areas populated by CD8+ T cells are enriched for specific lipids but deprived of glucose. Next, the authors demonstrated that CD8+ T cells within these areas accumulated free fatty acids that induced severe mitochondrial defects and functional exhaustion during tumor progression. RNA sequencing revealed that CD8+ T cells sorted from late tumors (in comparison with early tumors) showed reduced expression of ACADVL. This gene encodes very-long-chain acyl-CoA dehydrogenase (VLCAD), the enzyme catalyzing the first step of mitochondrial fatty acid oxidation, which is key to metabolizing lipids. Therefore, the authors engineered T cells to overexpress ACADVL with the aim of improving the metabolic fitness and persistence of CD8+ T cells within the tumor microenvironment. As anticipated, T cells with enforced ACADVL expression showed increased mitochondrial metabolic fitness and survival benefit upon adoptive transfer into tumor-bearing mice. Last, Manzo et al. confirmed that human pancreatic ductal adenocarcinoma tumors also accumulate lipids, and they performed single-cell RNA sequencing and multispectral imaging to demonstrate that human tumor-infiltrating CD8+ T cells also show an exhausted phenotype that is accompanied by reduced ACADVL expression.

Although the researchers were able to promote the survival of CD8+ T cells in a hostile microenvironment, enforcing ACADVL expression alone may not be sufficient to tackle the suppressed immune function of these cells. It remains to be demonstrated whether this metabolic intervention would further impede tumor progression when combined with checkpoint inhibition. An additional question for future studies is why specifically CD8+ T cells, in contrast to other immune cells within the tumor microenvironment, do not show the metabolic flexibility to survive the lipid-rich conditions.

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