Adrienne Luoma

• PhD, Immunology
• PostDoc Position at Dana-Farber Cancer Institute

The nature of the antigens recognized by γδ T cells and their potential recognition of major histocompatibility complex (MHC)-like molecules has remained unclear. Members of the CD1 family of lipid-presenting molecules are suggested ligands for Vδ1 TCR-expressing γδ T cells, the major γδ lymphocyte population in epithelial tissues. We crystallized...

γδ T cells are a prominent epithelial-resident lymphocyte population, possessing multi-functional capacities in the repair of host tissue, pathogen clearance, and tumor surveillance. Although three decades have now passed since their discovery, the nature of γδ T cell receptor (TCR)-mediated ligand recognition remains poorly defined. Recent studies...

Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisi...

The MHC fold is found in proteins that have a range of functions in the maintenance of an organism's health, from immune regulation to fat metabolism. Well adapted for antigen presentation, as seen for peptides in the classical MHC molecules and for lipids in CD1 molecules, the MHC fold has also been modified to perform Fc-receptor activity (e.g.,...

αβ T-cell lines specific for sulfatide, an abundant myelin glycosphingolipid presented by various CD1 molecules, have been previously derived from PBMCs of patients with demyelinating diseases such as multiple sclerosis (MS) but also from healthy subjects. Using an unbiased tetramer-based MACS enrichment method to enrich for rare antigen-specific c...

The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T-cells in multiple human solid tumor types, and its ligand CLEC2D is expressed by both tumor cells and infiltrating myeloid cells. Here we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Li...

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunoth...

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (T...

Brain metastases are the most frequent malignancies in the brain and are associated with significant morbidity and mortality. Melanoma brain metastases (MBM) occur in most patients with advanced melanoma and are challenging to treat. Our understanding of the treatment-naïve landscape of MBM is still rudimentary, and there are no site-specific molec...

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcr...

Immune surveillance cells such as T cells and phagocytes utilize integral plasma membrane receptors to recognize surface signatures on triggered and activated cells such as those in apoptosis. One such family of plasma membrane sensors, the transmembrane immunoglobulin and mucin domain (Tim) proteins, specifically recognize phosphatidylserine (PS)...

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, yet the host response at the lung tissue-level is poorly understood. Here, we performed single-nucleus RNA-sequencing of ~116,000 nuclei of lungs from 19 COVID-19 decedents who underwent rapid autopsy and 7 control lungs. Integrated analyses revealed...

Significance TCR mechanosensing is thought necessary for digital sensitivity of αβT cell response to scant pMHC antigens. We use bioinformatic analysis, molecular dynamics, single-molecule optical tweezers techniques, cellular activation, and RNA-seq analysis to explore this paradigm in the γδT cell lineage. We find that, in keeping with its role i...

Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classi...

CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition up...

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcr...

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almo...

Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)–Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-deri...

During the past decade, immunotherapies have made a major impact on the treatment of diverse types of cancer. Inflammatory toxicities are not only a major concern for Food and Drug Administration (FDA)-approved checkpoint blockade and chimeric antigen receptor (CAR) T cell therapies, but also limit the development and use of combination therapies....

Tumor-infiltrating myeloid-derived suppressor cells (MDSCs) are associated with poor survival outcomes in many human cancers. MDSCs inhibit T cell-mediated tumor immunity in part because they strongly inhibit T-cell function. However, whether MDSCs inhibit early or later steps of T-cell activation is not well established. Here we showed that MDSCs...

Resistance to immune checkpoint inhibitors (ICI) that activate T cell mediated anti-tumor immunity is a key challenge in cancer therapy, yet the underlying mechanisms remain poorly understood. To further elucidate those, we developed a new approach, Perturb-CITE-seq, for pooled CRISPR perturbation screens with multi-modal RNA and protein single-cel...

Importance Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immu...

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET...

BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we...

Resistance to cytotoxic T cells is frequently mediated by loss of MHC class I expression or IFNγ signaling in tumor cells, such as mutations of B2M or JAK1 genes. NK cells could potentially target such resistant tumors, but suitable NK cell-based strategies remain to be developed. We hypothesized that such tumors could be targeted by NK cells if su...

Patients with melanoma resistant to RAF/MEK inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small-molecule CX-6258 has potent a...

NK cells contribute to protective antitumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we performed single-cell RNA-seq analysis of NK cells isolated from human melanoma metastases, including lesions from patients who had progressed following checkpoint blockade. This analysis...

The ability of the immune system to eliminate and shape the immunogenicity of tumours defines the process of cancer immunoediting¹. Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumours and have resulted in durable responses in patients with cancer that did not respond to...

Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote...

Stressed gut epithelium gets some relief Immunoglobulin A (IgA) is the most abundantly expressed antibody isotype and can be found at various mucosal surfaces in the body, including the gastrointestinal (GI) tract. IgA is polyreactive and can coat and restrain both commensal bacteria and enteric pathogens. Grootjans et al. found that endoplasmic re...

Immune checkpoint inhibitors (ICI) produce durable responses in some melanoma patients, but many patients derive no clinical benefit. The molecular underpinnings of ICI resistance involve intricate cell-cell interactions that are yet elusive. To systematically map the interactions between malignant and immune cells in the tumor ecosystem, we applie...

Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T-cells, the central effectors of antitumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T-cells, inc...

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states th...

A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain–derived class II–associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-A g7 even in the absence of DM, and this property is related to the type 1 diabetes–associated β57 polymorphism. We generated knock-in non-obese diabetic...

Helping NK cells find their way MICA and MICB proteins can be expressed on tumors and act as “kill me” signals to the immune system. But tumors often disguise themselves by shedding these proteins, which prevents specialized natural killer (NK) cells from recognizing and destroying the cancer. Ferrari de Andrade et al. engineered antibodies directe...

In this Letter, the 'Data availability' section in the Methods should state 'WES and RNA-seq data are deposited in dbGaP (https://www.ncbi.nlm. nih.gov/projects/gap/cgi-bin/study.cgi?study-id=phs001451.v1.p1).All other data are available from the corresponding author upon easonable request.' instead of 'All data are available from the corresponding...

SNF'ing out antitumor immunity Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor ce...

T cell/transmembrane immunoglobulin mucin protein 1, 3, and 4 (TIM1, TIM3, and TIM4) are vital regulators in the innate immune system. Their activation involves specifically binding phosphatidylserine (PS) exposed cell membranes. Elucidation of the detailed mechanism of this TIMs/lipid interaction is key to understanding their immunological functio...

The structure and amino acid diversity of the T-cell receptor (TCR), similar in nature to that of Fab portions of antibodies, would suggest that these proteins have a nearly infinite capacity to recognize antigen. Yet all currently defined native T cells expressing an α and β chain in their TCR can only sense antigen when presented in the context o...

The γδ T cell lineage in humans remains much of an enigma due to the low number of defined antigens, the non-canonical ways in which these cells respond to their environment and difficulty in tracking this population in vivo. In this review, we survey a comparative evolutionary analysis of the primate V, D and J gene segments and contrast these fin...

Reactive oxygen species (ROS) are implicated in a range of degenerative conditions, including aging, neurodegenerative diseases, and neurological disorders. Myelin is a lipid-rich multilamellar sheath that facilitates rapid nerve conduction in vertebrates. Given the high energetic demands and low antioxidant capacity of the cells that elaborate the...

GM1-gangliosidosis is a glycosphingolipid lysosomal storage disease involving accumulation of GM1 and its asialo form (GA1) primarily in the brain. Thin-layer chromatography and X-ray diffraction were used to analyze the lipid content/composition and the myelin structure of the optic and sciatic nerves from 7- and 10-month old β-galactosidase (β-ga...

Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue...

Significance Mucosal-associated invariant T (MAIT) cells are a highly conserved lineage of αβ T cells found in most mammals. These cells express a T-cell receptor of low diversity that recognizes vitamin metabolites presented by the MHC-related protein, MR1. Despite the evolutionary divergence of MR1 from other MHC proteins, we have found that MAIT...

Myelination requires a massive increase in glial cell membrane synthesis. Here, we demonstrate that the acute phase of myelin lipid synthesis is regulated by sterol regulatory element-binding protein (SREBP) cleavage activation protein (SCAP), an activator of SREBPs. Deletion of SCAP in Schwann cells led to a loss of SREBP-mediated gene expression...

Monitoring pathology/regeneration in experimental models of de-/remyelination requires an accurate measure not only of functional changes but also of the amount of myelin. We tested whether X-ray diffraction (XRD), which measures periodicity in unfixed myelin, can assess the structural integrity of myelin in fixed tissue. From laboratories involved...

Charcot-Marie-Tooth disease type 1B (CMT1B), a peripheral neuropathy, is caused by mutations in MPZ, the gene encoding protein zero (P0), the major integral protein of PNS myelin. An adhesive protein, P0 plays a significant role during elaboration and maintenance of multilamellar myelin. P0 mutation Arg69Cys (R69C) causes a severe early-onset form...

Myelination requires a massive increase in glial cell membrane synthesis. Here, we demonstrate that the acute phase of myelin lipid synthesis is regulated by sterol regulatory element-binding protein (SREBP) cleavage activation protein (SCAP), an activator of SREBPs. Deletion of SCAP in Schwann cells led to a loss of SREBP-mediated gene expression...