Paper Reading
01
PTPN2 regulates thegeneration of exhausted CD8+T cell subpopulations and restrainstumor immunity
Martin W. LaFleur, Thao H. Nguyen, et al
Nature Immunology,
CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. The progenitor population of exhausted cells, defined as programmed cell death PD-1int, CXCR5+ or Slamf6+, possesses enhanced proliferative capacity and polyfunctional cytokine production and serves as a reservoir of cells for the terminally exhausted population. The terminally exhausted population is defined as PD-1hi or Tim-3+ and is cytotoxic, albeit having reduced proliferative capacity, longevity and polyfunctional cytokine production. Eomes, Id2, Runx3, T cell receptor (TCR) stimulation, interleukin (IL)-2, IL-21, IL-12 and type 1 interferon (IFN)-I promote the formation of the terminally exhausted subpopulation, whereas Tbet, Tcf7, and Bcl6 enhance the formation of the progenitor exhausted subpopulation. During responses to PD-1 immune checkpoint blockade (ICB), the progenitor population expands and gives rise to the terminally exhausted subset.
It has been proven that PTPN2 has a cell-intrinsic role in CD8+ T cells in tumors, limiting their accumulation and expression of granzyme B. In this paper, the authors demonstrated that the deletion of Ptpn2 in CD8+ T cells enhances anti-tumor immunity by increasing the formation of the Tim-3+ subset. Ptpn2 deletion leads to enhanced IFN-I signaling, which is required for the early competitive advantage seen in Ptpn2-deleted CD8+T cells, as well as the enhanced early differentiation of Slamf6+Tim-3 cells into Slamf6+Tim-3+ and Slamf6–Tim-3+ cells. These findings are consistent with IFN-I signaling attenuating the TCF1–Bcl6 axis during LCMV infection, resulting in an increase in the percentage of Tim-3+ cells, and highlight a crucial role for IFN-I signaling early in the differentiation of terminally exhausted cells. Moreover, they also find an essential role for IL-2 in vitro for enhancing Tim-3+ subset formation in Ptpn2-deleted cells, where it likely works in conjunction with IFN-α to support proliferation.
This is consistent with a requirement for the proliferation of CXCR5+ progenitor cells to differentiate into Tim-3+ terminally exhausted cells during LCMV clone 13 infection.
It is believed that an increase in the progenitor"s exhausted subpopulation promotes the efficacy of PD-1 ICB in chronic infection and cancer. However, Tim-3+ subpopulation is the primary cytotoxic population. It is likely that both progenitor exhausted and terminally exhausted cells are required for an effective immune response that balances cytotoxic potential and longevity. Ptpn2 deletion causes an early increase in the cytotoxic Tim-3+ subpopulation without altering the number of progenitor Slamf6+ CD8+ T cells. This occurs because: (1) Ptpn2-deleted Slamf6+ cells have increased conversion into Tim-3+ cells; (2) Ptpn2-deleted Slamf6+ cells have increased proliferative capacity and thus can replenish the Slamf6+ cell pool; and (3) Ptpn2-deleted Tim-3+ cells have increased proliferative capacity, which further expands their numbers.
/10.1038/s41590-019-0480-4
02
OncolyticViruses Engineeredto Enforce Leptin ExpressionReprogramTumor-InfiltratingT CellMetabolism andPromote Tumor Clearance
Dayana B. Rivadeneira, Kristin DePeaux, et al.
Immunity,
It is now appreciated that the metabolism of both T cells and tumor cells represent key mechanisms limiting immune function against cancer. Cancer cells become metabolically deregulated, depleting the local environment of essential nutrients and producing an excess of potentially toxic by-products. In addition, tumor-infiltrating T cells acquire significant metabolic insufficiencies, including repressed glucose uptake and the loss of functional mitochondria. Thus, T cells are rendered insufficient in an environment that produces hypoxia and nutrient stress. Leptin is a canonical adipokine with potent metabolic reprogramming functions such as the promotion of glucose and fatty oxidation and mitochondrial biogenesis. Previous studies have shown that immune cells express theleptin receptor and that leptin as a cytokine can have pro-inflammatory functions in innate and adaptive immune responses. Moreover, there are some observations that leptin may inhibit regulatory T cell proliferation and function in models of inflammation and the autoimmunity.
In this paper, the authors demonstrated that there is an increase in leptin receptor expression in T cells in the tumor microenvironment compared to those in the secondary lymphoid organs. Leptin can metabolicallyenhance tumor-infiltrating T cell effector function through the persistence of mitochondrial function and an increase in oxidative phosphorylation. Single-cell RNA sequencing revealed that oncolytic viruses promote the infiltration of a robust tumor infiltrate, but one that is ultimately ineffective at promoting complete responses, due in part to metabolic insufficiency. Using a melanoma model in which leptin is locally elevated in the tumor microenvironment, they showed potent T cell activation and tumor control that was linked to metabolic reprogramming.
Thus, the oncolytic Vaccinia virus to genetically express leptin in order to deliver it to the tumor microenvironment was engineered. This therapy resulted in complete therapeutic responses, compared to the partial responses obtained with wild-type oncolytic virus. This study opens up the possibility
of further expanding the repertoire of metabolic modulators, among the myriad encoded in the genome that can be delivered directly into the tumor.
/10.1016/j.immuni..07.003
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