PI3Kγ is a molecular switch that controls immune suppression

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer1,2,3,4,5. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors1,2,3,4,5,6,7. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders

The Four types of Tregs in malignant lymphomas

Regulatory T cells (Tregs) are a specialized subpopulation of CD4+ T cells, which act to suppress the activation of other immune cells. Tregs represent important modulators for the interaction between lymphomas and host microenvironment. Lymphomas are a group of serious and frequently fatal malignant diseases of lymphocytes. Recent studies revealed that some lymphoma T cells might adopt a Treg profile. Assessment of Treg phenotypes and genotypes in patients may offer prediction of outcome in many types of lymphomas including diffuse large B-cell lymphoma, follicular lymphoma, cutaneous T cell lymphoma, and Hodgkin's lymphoma. Based on characterized roles of Tregs in lymphomas, we can categorize the various roles into four groups: (a) suppressor Tregs; (b) malignant Tregs; (c) direct tumor-killing Tregs; and (d) incompetent Tregs. The classification into four groups is significant in predicting prognosis and designing Tregs-based immunotherapies for treating lymphomas. In patients with lymphomas where Tregs serve either as suppressor Tregs or malignant Tregs, anti-tumor cytotoxicity is suppressed thus decreased numbers of Tregs are associated with a good prognosis. In contrast, in patients with lymphomas where Tregs serve as tumor-killing Tregs and incompetent Tregs, anti-tumor cytotoxicity is enhanced or anti-autoimmune Tregs activities are weakened thus increased numbers of Tregs are associated with a good prognosis and reduced numbers of Tregs are associated with a poor prognosis. However, the mechanisms underlying the various roles of Tregs in patients with lymphomas remain unknown. Therefore, further research is needed in this regard as well as the utility of Tregs as prognostic factors and therapy strategies in different lymphomas

Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

Neurotrophins and their respective tropomyosin related kinase (Trk) receptors (TrkA, TrkB, and TrkC) and the p75 neurotrophin receptor (p75(NTR)) play a fundamental role in the development and maintenance of the nervous system making them important targets for treatment of neurodegenerative diseases. Whereas Trk receptors are directly activated by specific neurotrophins, the p75(NTR) is a multifunctional receptor that exerts its effects via heterodimeric interactions with TrkA, TrkB, TrkC, sortilin or the Nogo receptor to regulate a wide array of cellular functions. By partnering with different receptors the p75(NTR) regulates binding of mature versus pro-neurotrophins and activation of different signaling pathways with outcomes ranging from growth and survival to cell death. While the developmental downregulation of the p75(NTR) has raised questions regarding its role in the mature nervous system, recent data have revealed widespread expression of low levels, a role in synaptic plasticity and adult neurogenesis and upregulation in response to injury or disease. Studies are needed to better understand these processes, particularly in the damaged nervous system, but will be complicated by expression of p75(NTR) on immune cells including macrophages and microglia that are intimately involved in disease and repair processes. Recent approaches that regulate p75(NTR) function with small non-peptide ligands have demonstrated potent neuroprotection in models of injury and neurodegenerative diseases that highlight the importance of the p75(NTR) as a therapeutic target. Future studies hold the promise of revealing a wealth of information on the multifaceted actions of the p75(NTR) that will inform the design of new neurotrophin-based therapies