Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.

CD8 T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (T) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid.

Tim-3 Is Required for Regulatory T Cell-Mediated Promotion of T Cell Exhaustion and Viral Persistence during Chronic Lymphocytic Choriomeningitis Virus Infection.

Expression of T cell Ig and mucin domain-containing protein 3 (Tim-3) is upregulated on regulatory T cells (Tregs) during chronic viral infections. In several murine and human chronic infections, the expression of Tim-3 is associated with poor control of viral burden and impaired antiviral immune responses. However, the role of Tim-3+ Tregs during persistent viral infections has not been fully defined.

Treatment with oncolytic vaccinia virus infects tumor-infiltrating regulatory and exhausted T cells.

Background: Oncolytic viruses (OVs) are an attractive way to increase immune infiltration into an otherwise cold tumor. While OVs are engineered to selectively infect tumor cells, there is evidence that they can infect other non-malignant cells in the tumor. We sought to determine if oncolytic vaccinia virus (VV) can infect lymphocytes in the tumor and, if so, how this was linked to therapeutic efficacy.

LAG-3 and PD-1 synergize on CD8 T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.

Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown.

An IRF2-Expressing Oncolytic Virus Changes the Susceptibility of Tumor Cells to Antitumor T Cells and Promotes Tumor Clearance.

IFN regulatory factor 1 (IRF1) can promote antitumor immunity. However, we have shown previously that in the tumor cell, IRF1 can promote tumor growth, and IRF1-deficient tumor cells exhibit severely restricted tumor growth in several syngeneic mouse tumor models. Here, we investigate the potential of functionally modulating IRF1 to reduce tumor progression and prolong survival.

Metabolic waypoints during T cell differentiation.

This Review explores the interplay between T cell activation and cell metabolism and highlights how metabolites serve two pivotal functions in shaping the immune response. Traditionally, T cell activation has been characterized by T cell antigen receptor-major histocompatibility complex interaction (signal 1), co-stimulation (signal 2) and cytokine signaling (signal 3). However, recent research has unveiled the critical role of metabolites in this process.

Redox and detox: Malate shuttle metabolism keeps exhausted T cells fit.

The malate shuttle is known to maintain the balance of NAD/NADH between the cytosol and mitochondria. However, in T cells, it primarily detoxifies ammonia (via GOT1-mediated production of 2-KG in an atypical reaction) and provides longevity to chronic-infection-induced T cells against ammonia-induced cell death.

Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.

Clinical studies report that viral infections promote acute or chronic bacterial infections at multiple host sites. These viral-bacterial co-infections are widely linked to more severe clinical outcomes. In experimental models in vitro and in vivo, virus-induced interferon responses can augment host susceptibility to secondary bacterial infection.

Integrating innate and adaptive immunity in oncolytic virus therapy.

Oncolytic viruses (OVs), viruses engineered to lyse tumor cells, work hand in hand with the immune response. While for decades the field isolated lytic capability and viral spread to increase response to virotherapy, there is now a wealth of research that demonstrates the importance of immunity in the OV mechanism of action. In this review, we will cover how OVs interact with the innate immune system to fully activate the adaptive immune system and yield exceptional tumor clearances as well as look forward at combination therapies which can improve clinical responses.

An oncolytic virus-delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment.

While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants of the murine HNSCC model MEER. While entirely αPD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV).

Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.

Background: Cellular immunotherapies for cancer represent a means by which a patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral T cells to tumor targets, showing remarkable potency in blood cancers. However, due to several resistance mechanisms, CAR-T cell therapies remain ineffective in solid tumors.

The schedule of ATR inhibitor AZD6738 can potentiate or abolish antitumor immune responses to radiotherapy.

Inhibitors of the DNA damage signaling kinase ATR increase tumor cell killing by chemotherapies that target DNA replication forks but also kill rapidly proliferating immune cells including activated T cells. Nevertheless, ATR inhibitor (ATRi) and radiotherapy (RT) can be combined to generate CD8+ T cell-dependent antitumor responses in mouse models. To determine the optimal schedule of ATRi and RT, we determined the impact of short-course versus prolonged daily treatment with AZD6738 (ATRi) on responses to RT (days 1-2).

Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity.

CD8 T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy.

Fully murine CD105-targeted CAR-T cells provide an immunocompetent model for CAR-T cell biology.

The modeling of chimeric antigen receptor (CAR) T cell therapies has been mostly focused on immunodeficient models. However, there are many advantages in studying CAR-T cell biology in an immunocompetent setting. We generated a fully murine CAR targeting CD105 (endoglin), a component of the TGFβ receptor expressed on the surface of certain solid tumors and acute leukemias.

Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.

Purpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).

Experimental Design: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts.

Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells.

Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8 T cells throughout differentiation.