Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways.

The discovery and clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1 and PD-L1 has revolutionized the treatment of cancer, as recognized by the 2018 Nobel Prize for Medicine and Physiology. This groundbreaking new approach has improved the outcomes of patients with various forms of advanced-stage cancer; however, the majority of patients receiving these therapies, even in combination, do not derive clinical benefit. Further development of agents targeting additional immune checkpoints, co-stimulatory receptors and/or co-inhibitory receptors that control T cell function is therefore critical. In this Review, we discuss the translational potential and clinical development of agents targeting both co-stimulatory and co-inhibitory T cell receptors. Specifically, we describe their mechanisms of action, and provide an overview of ongoing clinical trials involving novel ICIs including those targeting LAG3, TIM3, TIGIT and BTLA as well as agonists of the co-stimulatory receptors GITR, OX40, 41BB and ICOS. We also discuss several additional approaches, such as harnessing T cell metabolism, in particular via adenosine signalling, inhibition of IDO1, and targeting changes in glucose and fatty acid metabolism. We conclude that further efforts are needed to optimize the timing of combination ICI approaches and, most importantly, to individualize immunotherapy based on both patient-specific and tumour-specific characteristics.

Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine.

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.

Immunoengineering in glioblastoma imaging and therapy.

Patients diagnosed with glioblastoma have poor prognosis. Conventional treatment strategies such as surgery, chemotherapy, and radiation therapy demonstrated limited clinical success and have considerable side effects on healthy tissues. A central challenge in treating brain tumors is the poor permeability of the blood-brain barrier (BBB) to therapeutics. Recently, various methods based on immunotherapy and nanotechnology have demonstrated potential in addressing these obstacles by enabling precise targeting of brain tumors to minimize adverse effects, while increasing targeted drug delivery across the BBB. In addition to treating the tumors, these approaches may be used in conjunction with imaging modalities, such as magnetic resonance imaging and positron emission tomography to enhance the prognosis procedures. This review aims to provide mechanistic understanding of immune system regulation in the central nervous system and the benefits of nanoparticles in the prognosis of brain tumors. This article is characterized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Cells at the Nanoscale Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Association Between Thyroid Disorders and Colorectal Cancer Risk in Adult Patients in Taiwan.

Importance: Thyroid hormones have been shown to affect several important pathways in cancer development, including colorectal cancer (CRC). Clinical studies examining the association between thyroid disorders and colorectal cancer have conflicting results and have predominantly involved white populations. Objective: To determine if a diagnosis of hyperthyroidism or hypothyroidism is associated with the risk of developing colorectal cancer in an East Asian population. Design, Setting, and Participants: This nationwide population-based case-control study was conducted from April 27, 2018, to November 8, 2018, using the Taiwanese National Health Insurance Research Database. Participants were adults (n = 139 426) either with a new diagnosis (between 2008 and 2013) of primary colorectal cancer without a history of cancer, or without cancer. Cases and controls were matched 1:1 by age, sex, and index date. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of colorectal cancer (or the same index date in controls) was then determined. Main Outcomes and Measures: Risk differences in developing colorectal cancer among patients with a medical history of hyperthyroidism or hypothyroidism. Results: A total of 139 426 patients were included in the study, and 69 713 individuals made up each case and control group, which were both predominantly male (39 872 [57.2%]). The mean (SD) age for those with CRC was 65.8 (13.7) years and for those without CRC was 66.0 (13.6) years. Both hyperthyroidism (adjusted odds ratio [aOR], 0.77; 95% CI, 0.69-0.86; P < .001) and hypothyroidism (aOR, 0.78; 95% CI, 0.65-0.94; P = .008) were associated with a decreased risk of being diagnosed with colorectal cancer. An inverse association of rectal cancer was found among patients aged 50 years or older with a history of hypothyroidism despite treatment (aOR, 0.54; 95% CI, 0.39-0.74; P < .001). A history of hyperthyroidism in all age groups was associated with a lower risk of colon cancer (aOR, 0.74; 95% CI, 0.64-0.85; P < .001), with a stronger association seen among those younger than 50 years (aOR, 0.55; 95% CI, 0.36-0.85; P = .007). Conclusions and Relevance: In this study, hypothyroidism appeared to be associated with a lower risk of rectal cancer, whereas hyperthyroidism appeared to be associated with a lower risk of colon cancer. Because of this, biochemical in vivo research and epidemiologic studies appear to be needed to further clarify the nature of these associations.

Cigarette smoke inhibits ROCK2 activation in T cells and modulates IL-22 production.

Gene-environment interactions are known to play a key role in the development of rheumatoid arthritis (RA). Exposure to cigarette smoke (CS) is one of the strongest environmental risk factors associated with RA and has been shown to mediate a range of complex immunomodulatory effects from decreased T and B cell activation to depressed phagocytic function. The effects of CS on the function of TH17 cells, one of the key TH effector subsets implicated in RA pathogenesis, are not fully understood. IRF4 is one of the crucial transcription factors involved in TH-17 differentiation and is absolutely required for the production of IL-17 and IL-21 but, interestingly, inhibits the synthesis of IL-22. The production of IL-17 and IL-21 by IRF4 can be augmented by its phosphorylation by the serine-threonine kinase ROCK2. Given that CS has been reported to increase ROCK activity in endothelial cells, here we investigated the effects of CS on the ROCK2-IRF4 axis in T cells. Surprisingly, we found that CS leads to decreased ROCK2 activation and IRF4 phosphorylation in T cells. This effect was associated with increased IL-22 production. Using a GEF pull-down assay we furthermore identify ARHGEF1 as a key upstream regulator of ROCK2 whose activity in T cells is inhibited by CS. Thus CS can inhibit the ROCK2-IRF4 axis and modulate T cell production of IL-22.

Rho Kinases in Autoimmune Diseases.

The Rho kinases, or ROCKs, are a family of serine-threonine kinases that serve as key downstream effectors for Rho GTPases. The ROCKs are increasingly recognized as critical coordinators of a tissue response to injury due to their ability to modulate a wide range of biological processes. Dysregulated ROCK activity has been implicated in several human pathophysiological conditions ranging from cardiovascular and renal disorders to fibrotic diseases. In recent years, an important role for the ROCKs in the regulation of immune responses is also being uncovered. We provide an overview of the role of the ROCKs in immune cells and discuss studies that highlight the emerging involvement of this family of kinases in the pathogenesis of autoimmune diseases. Given the potential promise of the ROCKs as therapeutic targets, we also outline the approaches that could be employed to inhibit the ROCKs in autoimmune disorders.

Regulation of Effector Treg Cells in Murine Lupus.

OBJECTIVE: Treg cells need to acquire an effector phenotype to function in settings of inflammation. Whether effector Treg cells can limit disease severity in lupus is unknown. Interferon regulatory factor 4 (IRF-4) is an essential controller of effector Treg cells and regulates their ability to express interleukin-10 (IL-10). In non-Treg cells, IRF-4 activity is modulated by interactions with DEF-6 and its homolog switch-associated protein 70 (SWAP-70). Although mice lacking both DEF-6 and SWAP-70 (double-knockout [DKO] mice) develop lupus, they display normal survival, suggesting that in DKO mice, Treg cells can moderate disease development. The purpose of this study was to investigate whether Treg cells from DKO mice have an increased capacity to become effector Treg cells due to the ability of DEF-6 and SWAP-70 to restrain IRF-4 activity. METHODS: Treg cells were evaluated by fluorescence-activated cell sorting. The B lymphocyte-induced maturation protein 1 (BLIMP-1)/IL-10 axis was assessed by crossing DKO mice with BLIMP-1-YFP-10BiT dual-reporter mice. Deletion of IRF-4 in Treg cells from DKO mice was achieved by generating FoxP3(Cre) IRF-4(fl/fl) DKO mice. RESULTS: The concomitant absence of DEF-6 and SWAP-70 led to increased numbers of Treg cells, which acquired an effector phenotype in a cell-intrinsic manner. In addition, Treg cells from DKO mice exhibited enhanced expression of the BLIMP-1/IL-10 axis. Notably, DKO effector Treg cells survived and expanded as disease progressed. The accumulation of Treg cells from DKO mice was associated with the up-regulation of genes controlling autophagy. IRF-4 was required for the expansion and function of effector Treg cells from DKO mice. CONCLUSION: This study revealed the existence of mechanisms that, by acting on IRF-4, can fine-tune the function and survival of effector Treg cells in lupus. These findings suggest that the existence of a powerful effector Treg cell compartment that successfully survives in an unfavorable inflammatory environment could limit disease development.