Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy.

Multiplexed Spatial Profiling of Hodgkin Reed-Sternberg Cell Neighborhoods in Classic Hodgkin Lymphoma.

Purpose: Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1%-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of nonmalignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown.

Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors.

Tumor-specific CD8 T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4 T cells can be enlisted to overcome CD8 T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8 and CD4 T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4 T cells must engage with CD8 T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8 T cell cytotoxicity and cancer cell elimination.

A replicating LCMV-based vaccine for the treatment of solid tumors.

Harnessing the immune system to eradicate tumors requires identification and targeting of tumor antigens, including tumor-specific neoantigens and tumor-associated self-antigens. Tumor-associated antigens are subject to existing immune tolerance, which must be overcome by immunotherapies. Despite many novel immunotherapies reaching clinical trials, inducing self-antigen-specific immune responses remains challenging.

GABA Regulates Electrical Activity and Tumor Initiation in Melanoma.

Unlabelled: Oncogenes can initiate tumors only in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E.

Intratumoral immune triads are required for adoptive T cell therapy-mediated elimination of solid tumors.

Tumor-reactive CD8 T cells found in cancer patients are frequently dysfunctional, unable to halt tumor growth. Adoptive T cell transfer (ACT), the administration of large numbers of -generated cytolytic tumor-reactive CD8 T cells, is an important cancer immune therapy being pursued. However, a limitation of ACT is that transferred CD8 T cells often rapidly lose effector function, and despite exciting results in certain malignancies, few ACT clinical trials have shown responses in solid tumors.

Ovarian cancer mutational processes drive site-specific immune evasion.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, tumour heterogeneity and intraperitoneal spread. Immunotherapies have had limited efficacy in HGSOC, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC.

Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging.

The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples.

Noninvasive Imaging of CD4+ T Cells in Humanized Mice.

Antibody-based PET (immunoPET) with radiotracers that recognize specific cells of the immune system provides an opportunity to monitor immune cell trafficking at the organismal scale. We previously reported the visualization of human CD8+ T cells, including CD8+ tumor-infiltrating lymphocytes (TIL), in mice using a humanized CD8-targeted minibody. Given the important role of CD4+ T cells in adaptive immune responses of health and disease including infections, tumors, and autoimmunity, we explored immunoPET using an anti-human-CD4 minibody.

Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma.

Cancer immunotherapy can result in lasting tumor regression, but predictive biomarkers of treatment response remain ill-defined. Here, we performed single-cell proteomics, transcriptomics, and genomics on matched untreated and IL2 injected metastases from patients with melanoma. Lesions that completely regressed following intralesional IL2 harbored increased fractions and densities of nonproliferating CD8+ T cells lacking expression of PD-1, LAG-3, and TIM-3 (PD-1-LAG-3-TIM-3-).

TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion.

T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program.

An autoimmune stem-like CD8 T cell population drives type 1 diabetes.

CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells. How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown. In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells.

Ectopic activation of the miR-200c-EpCAM axis enhances antitumor T cell responses in models of adoptive cell therapy.

Adoptive T cell therapy (ACT) is a promising strategy for treating cancer, but it often fails because of cell intrinsic regulatory programs that limit the degree or duration of T cell function. In this study, we found that ectopic expression of microRNA-200c (miR-200c) markedly enhanced the antitumor activity of CD8 cytotoxic T lymphocytes (CTLs) during ACT in multiple mouse models. CTLs transduced with miR-200c exhibited reduced apoptosis during engraftment and enhanced in vivo persistence, accompanied by up-regulation of the transcriptional regulator T cell factor 1 (TCF1) and the inflammatory cytokine tumor necrosis factor (TNF).

CD8 T cell differentiation and dysfunction in cancer.

CD8 T cells specific for cancer cells are detected within tumours. However, despite their presence, tumours progress. The clinical success of immune checkpoint blockade and adoptive T cell therapy demonstrates the potential of CD8 T cells to mediate antitumour responses; however, most patients with cancer fail to achieve long-term responses to immunotherapy.

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [Cu]Cu-NOTA-anti-CD8 PET.

Purpose: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8) T cells using PET.

An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection.

Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines. Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection and, independently, in eliciting a measurable CD8 response. This analysis uncovered a large trove of effective anticancer neoepitopes that have strikingly different properties from conventional epitopes and suggested an algorithm to predict them.

Exercise and immunometabolic regulation in cancer.

Unhealthful lifestyle factors, such as obesity, disrupt organismal homeostasis and accelerate cancer pathogenesis, partly through metabolic and immunological dysregulation. Exercise is a prototypical strategy that maintains and restores homeostasis at the organismal, tissue, cellular and molecular levels and can prevent or inhibit numerous disease conditions, including cancer. Here, we review unhealthful lifestyle factors that contribute to metabolic and immunological dysregulation and drive tumourigenesis, focusing on patient physiology (host)-tissue-tumour microenvironment interactions.

Mite Burden and Immunophenotypic Response to in Swiss Webster, BALB/c, C57BL/6, and NSG Mice.

Detection methods for were historically unreliable, and testing was rarely performed because its prevalence in laboratory mice was underestimated. Although infestations are unapparent in most mouse strains, burdens are higher and clinical signs detected in various immunodeficient strains. The parasite's influence on the immune system of immunocompetent mice is unknown.

Defining 'T cell exhaustion'.

'T cell exhaustion' is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours. Understanding the features of and pathways to exhaustion has crucial implications for the success of checkpoint blockade and adoptive T cell transfer therapies. In this Viewpoint article, 18 experts in the field tell us what exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection.

TOX is a critical regulator of tumour-specific T cell differentiation.

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection.

Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections.

CD8 T cell differentiation is a tightly regulated process generating effector and memory T cells over the course of acute infections. In cancer and chronic infection, this differentiation program is derailed, and antigen-specific CD8 T cells differentiate to a hyporesponsive state generally referred to as T cell exhaustion. Here, we review recent findings on heterogeneity of tumor-specific T cells and exhausted T cells during chronic infections, discussing distinct differentiation state dynamics, fate choices, and functional states.

Rejection of immunogenic tumor clones is limited by clonal fraction.

Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new 'PresentER' antigen presentation platform.