SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses.

The inhibitory receptor PD-1 suppresses T cell activation by recruiting the phosphatase SHP-2. However, mice with a T-cell-specific deletion of SHP-2 do not have improved antitumor immunity. Here we showed that mice with conditional targeting of SHP-2 in myeloid cells, but not in T cells, had diminished tumor growth.

Treatment with Exogenously Added Catalase Alters CD8 T Cell Memory Differentiation and Function.

Cell-based immunotherapy is a promising approach to cancer treatment. However, the metabolically hostile tumor microenvironment (TME) poses a major barrier to this therapeutic approach. Metabolic reprogramming may enhance T cell effector function and support longevity and persistence within the TME.

PD-1 T cells: a foe in cancer immunotherapy?

The mechanisms that drive responses to PD-1-blocking immunotherapy in some but not all patients have been puzzling. A new study suggests that the balance of PD-1 expression levels between CD8 T cells and T cells might provide an answer.

Publisher Correction: Phosphorylation of PD-1-Y248 is a marker of PD-1-mediated inhibitory function in human T cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

T Cell Metabolism in Cancer Immunotherapy.

Immune checkpoint therapies aiming to enhance T cell responses have revolutionized cancer immunotherapy. However, although a small fraction of patients develops durable anti-tumor responses, the majority of patients display only transient responses, underlying the need for finding auxiliary approaches. Tumor microenvironment poses a major metabolic barrier to efficient anti-tumor T cell activity.

Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation.

Programmed cell death-1 (PD-1) inhibits T cell responses. This function relies on interaction with SHP-2. PD-1 has one immunoreceptor tyrosine-based inhibitory motif (ITIM) at Y223 and one immunoreceptor tyrosine-based switch motif (ITSM) at Y248.

Phosphorylation of PD-1-Y248 is a marker of PD-1-mediated inhibitory function in human T cells.

PD-1 is a target of cancer immunotherapy but responses are limited to a fraction of patients. Identifying patients with T cells subjected to PD-1-mediated inhibition will allow selection of suitable candidates for PD-1-blocking therapy and will improve the therapeutic success. We sought to develop an approach to detect PD-1-mediated inhibitory signaling.

Targeting T Cell Metabolism for Improvement of Cancer Immunotherapy.

There has been significant progress in utilizing our immune system against cancer, mainly by checkpoint blockade and T cell-mediated therapies. The field of cancer immunotherapy is growing rapidly but durable clinical benefits occur only in a small subset of responding patients. It is currently recognized that cancer creates a suppressive metabolic microenvironment, which contributes to ineffective immune function.

Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation.

Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction.