Opportunities to Modulate Tumor Ecosystem Toward Successful Glioblastoma Immunotherapy.

Over the past decade, the failure of multiple clinical trials has confirmed the need for a systematic and comprehensive understanding of glioblastoma (GBM). Current immunotherapies aiming to harness the immune system to achieve anti-tumor effects remain largely ineffective, highlighting the complexities of the GBM microenvironment. However, our recent understanding of immune niches within the central nervous system provides both opportunities and challenges in translating these insights into successful immunotherapy implementation.

Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.

Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4 T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB).

Induced electric fields inhibit breast cancer growth and metastasis by modulating the immune tumor microenvironment.

Despite tremendous advances in oncology, metastatic triple-negative breast cancer remains difficult to treat and manage with established therapies. Here, we show in mice with orthotopic triple-negative breast tumors that alternating (100 kHz), and low intensity (<1 mV/cm) induced electric fields (iEFs) significantly reduced primary tumor growth and distant lung metastases. Non-contact iEF treatment can be delivered safely and non-invasively via a hollow, rectangular solenoid coil.

Steroid hormone regulation of immune responses in cancer.

Steroid hormones are derived from cholesterol and can be classified into sex hormones (estrogens, androgens, progesterone) that are primarily synthesized in the gonads and adrenal hormones (glucocorticoids and mineralocorticoids) that are primarily synthesized in the adrenal gland. Although, it has long been known that steroid hormones have potent effects on the immune system, recent studies have led to renewed interest in their role in regulating anti-tumor immunity. Extra-glandular cells, such as epithelial cells and immune cells, have been shown to synthesize glucocorticoids and thereby modulate immune responses in the tumor microenvironment.

Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function.

Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of therapeutic strategies for modulating the immune response in different disease contexts. Tim-3 plays an important role in regulating immune responses by inhibiting the activation status and the T cell priming ability of DC in the setting of cancer.

An IL-27-Driven Transcriptional Network Identifies Regulators of IL-10 Expression across T Helper Cell Subsets.

Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms, including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative (Irf9 and Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10.

Endogenous Glucocorticoid Signaling Regulates CD8 T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment.

Identifying signals in the tumor microenvironment (TME) that shape CD8 T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8 tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8 TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition.

Tim-3 finds its place in the cancer immunotherapy landscape.

The blockade of immune checkpoint receptors has made great strides in the treatment of major cancers, including melanoma, Hodgkin's lymphoma, renal, and lung cancer. However, the success rate of immune checkpoint blockade is still low and some cancers, such as microsatellite-stable colorectal cancer, remain refractory to these treatments. This has prompted investigation into additional checkpoint receptors.

New Clones on the Block.

Although immune checkpoint blockade (ICB) has yielded striking clinical responses in subsets of cancer patients, the mechanism of action is still unclear. In a recent issue of Nature Medicine, Yost et al., 2019 report that the T cell clones that dominate the intra-tumoral T cell landscape after ICB are distinct from those prior to treatment, a phenomenon referred to by the authors as "clonal replacement.

Induction and transcriptional regulation of the co-inhibitory gene module in T cells.

The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4 T cells promotes autoimmunity, whereas sustained overexpression on CD8 T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors.

Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy.

Both data in preclinical cancer models and data with T cells from patients with advanced cancer support a role for Tim-3 blockade in promoting effective anti-tumor immunity. Consequently, there is considerable interest in the clinical development of antibody-based therapeutics that target Tim-3 for cancer immunotherapy. A challenge to this clinical development is the fact that several ligands for Tim-3 have been identified: galectin-9, phosphatidylserine, HMGB1, and most recently, CEACAM1.

Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas.