Reduced bioenergetics in tumors and chronic infection lead to metabolic dysfunction and CD8+ T-cell exhaustion
Image : https://commons.wikimedia.org/wiki/File%3AMitochondria.svg. Nevit (own work)
In tumor microenvironments and during chronic inflammation, cytotoxic T cells become “exhausted.” Bengsch et al. and Scharping et al. found that the exhaustion involved repression of mitochondrial replication and energy production, orchestrated by reductions in PGC1α expression.
Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity
Image : https://commons.wikimedia.org/wiki/File:Medulloblastoma_HE_x200.jpg. Jensflorian (own work)
Cdk5 is expressed in medulloblastomas. Deleting Cdk5 allowed a potent CD4+ T cell–mediated tumor rejection to develop. The tumor immunoevasive mechanism evoked by interferon-γ that increases PD-L1 expression was suppressed in medulloblastomas that did not express Cdk5.
CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
When CD19 CAR T-cell therapy is used against ALL, the CD19 protein is often downregulated. This was found not to be the mere disappearance of an epitope, but represented cellular reprogramming and a switch to the myeloid lineage.
CXCR5+ CD8+ T cells in chronic infection proliferate upon PD-1 blockade
Image : https://commons.wikimedia.org/w/index.php?curid=4463752. Gleiberg (own work)
Less than 2% of CD8+ T cells express CXCR5. These cells were found to be generated in chronically infected animals and to have stem cell-like renewal properties. They could also differentiate into CXCR5− cells and proliferate extensively upon PD-1 blockade with checkpoint inhibitors.
Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche
Tumor metastasis requires the maintenance of favorable protumor niches. T cells use the oxygen-sensitive PHD proteins to regulate differentiation and effector function. In lung tumors, PHD proteins promoted T-cell localization and Treg proliferation and repressed antitumor activity.
Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis
Image : https://commons.wikimedia.org/w/index.php?curid=9051744. Nephron (own work)
T cells specific for tumors are often functionally disabled, and this has been attributed to the tumor microenvironment. Schietinger et al. found that this dysfunctional state is induced early in tumorigenesis, is intrinsic, and becomes irreversible over time.