ATXN3 functions as a tumor suppresser through potentiating Galectin-9-mediated apoptosis in human colon adenocarcinoma.

While the deubiquitinase ATXN3 has been implicated as a potential oncogene in various types of human cancers, its role in colon adenocarcinoma remains understudied. Surprisingly, our findings demonstrate that ATXN3 exerts an anti-tumor effect in human colon cancers through potentiating Galectin-9-induced apoptosis. CRISPR-mediated ATXN3 deletion unexpectedly intensified colon cancer growth both in vitro and in xenograft colon cancers. At the molecular level, we identified ATXN3 as a bona fide deubiquitinase specifically targeting Galectin-9, as ATXN3 interacted with and inhibited Galectin-9 ubiquitination. Consequently, targeted ATXN3 ablation resulted in reduced Galectin-9 protein expression, thereby diminishing Galectin-9-induced colon cancer apoptosis and cell growth arrest. The ectopic expression of Galectin-9 fully reversed the growth of ATXN3-null colon cancer in mice. Furthermore, immunohistochemistry staining revealed a significant reduction in both ATXN3 and Galectin-9 protein expression, along with a positive correlation between them in human colon cancer. Our study identifies the first Galectin-9-specific deubiquitinase and unveils a tumor-suppressive role of ATXN3 in human colon cancer.

Mediator complex subunit 1 architects a tumorigenic Treg cell program independent of inflammation.

While immunotherapy has revolutionized cancer treatment, its safety has been hampered by immunotherapy-related adverse events. Unexpectedly, we show that Mediator complex subunit 1 (MED1) is required for T regulatory (Treg) cell function specifically in the tumor microenvironment. Treg cell-specific MED1 deletion does not predispose mice to autoimmunity or excessive inflammation. In contrast, MED1 is required for Treg cell promotion of tumor growth because MED1 is required for the terminal differentiation of effector Treg cells in the tumor. Suppression of these terminally differentiated Treg cells is sufficient for eliciting antitumor immunity. Both human and murine Treg cells experience divergent paths of differentiation in tumors and matched tissues with non-malignant inflammation. Collectively, we identify a pathway promoting the differentiation of a Treg cell effector subset specific to tumors and demonstrate that suppression of a subset of Treg cells is sufficient for promoting antitumor immunity in the absence of autoimmune consequences.

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy.

Therapeutic antibodies have become one of the most influential therapeutics in modern medicine to fight against infectious pathogens, cancer, and many other diseases. However, experimental screening for highly efficacious targeting antibodies is labor-intensive and of high cost, which is exacerbated by evolving antigen targets under selective pressure such as fast-mutating viral variants. As a proof-of-concept, we developed a machine learning-assisted antibody generation pipeline that greatly accelerates the screening and re-design of immunoglobulins G (IgGs) against a broad spectrum of SARS-CoV-2 coronavirus variant strains. These viruses infect human host cells via the viral spike protein binding to the host cell receptor angiotensin-converting enzyme 2 (ACE2). Using over 1300 IgG sequences derived from convalescent patient B cells that bind with spike's receptor binding domain (RBD), we first established protein structural docking models in assessing the RBD-IgG-ACE2 interaction interfaces and predicting the virus-neutralizing activity of each IgG with a confidence score. Additionally, employing Gaussian process regression (also known as Kriging) in a latent space of an antibody language model, we predicted the landscape of IgGs' activity profiles against individual coronaviral variants of concern. With functional analyses and experimental validations, we efficiently prioritized IgG candidates for neutralizing a broad spectrum of viral variants (wildtype, Delta, and Omicron) to prevent the infection of host cells in vitro and hACE2 transgenic mice in vivo. Furthermore, the computational analyses enabled rational redesigns of selective IgG clones with single amino acid substitutions at the RBD-binding interface to improve the IgG blockade efficacy for one of the severe, therapy-resistant strains - Delta (B.1.617). Our work expedites applications of artificial intelligence in antibody screening and re-design even in low-data regimes combining protein language models and Kriging for antibody sequence analysis, activity prediction, and efficacy improvement, in synergy with physics-driven protein docking models for antibody-antigen interface structure analyses and functional optimization.

CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.

Informing immunotherapy with multi-omics driven machine learning.

Progress in sequencing technologies and clinical experiments has revolutionized immunotherapy on solid and hematologic malignancies. However, the benefits of immunotherapy are limited to specific patient subsets, posing challenges for broader application. To improve its effectiveness, identifying biomarkers that can predict patient response is crucial. Machine learning (ML) play a pivotal role in harnessing multi-omic cancer datasets and unlocking new insights into immunotherapy. This review provides an overview of cutting-edge ML models applied in omics data for immunotherapy analysis, including immunotherapy response prediction and immunotherapy-relevant tumor microenvironment identification. We elucidate how ML leverages diverse data types to identify significant biomarkers, enhance our understanding of immunotherapy mechanisms, and optimize decision-making process. Additionally, we discuss current limitations and challenges of ML in this rapidly evolving field. Finally, we outline future directions aimed at overcoming these barriers and improving the efficiency of ML in immunotherapy research.

Immune Assessment Today: Optimizing and Standardizing Efforts to Monitor Immune Responses in Cancer and Beyond.

As part of a symposium, current and former directors of Immune Monitoring cores and investigative oncologists presented insights into the past, present and future of immune assessment. Dr. Gnjatic presented a classification of immune monitoring technologies ranging from universally applicable to experimental protocols, while emphasizing the need for assay harmonization. Dr. Obeng discussed physiologic differences among CD8 T cells that align with anti-tumor responses. Dr. Lyerly presented the Soldano Ferrone lecture, commemorating the passionate tumor immunologist who inspired many, and covered a timeline of monitoring technology development and its importance to immuno-oncology. Dr. Sonabend presented recent achievements in glioblastoma treatment, accentuating the range of monitoring techniques that allowed him to refine patient selection for clinical trials. Dr. Guevara-Patiño focused on hypoxia within the tumor environment and stressed that T cell viability is not to be confused with functionality. Dr. Butterfield accentuated monitoring of dendritic cell metabolic (dys)function as a determinant for tumor vaccine success. Lectures were interspersed with select abstract presentations. To summarize the concepts, Dr. Maecker from Stanford led an informative forum discussion, pointing towards the future of immune monitoring. Immune monitoring continues to be a guiding light towards effective immunotherapeutic strategies.

CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1-positive regulator for tumor immune evasion.

Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α. Moreover, ATXN3 functioned as a deubiquitinase of the AP-1 transcription factor JunB, indicating that ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ- and hypoxia-induced PD-L1 expression and consequently enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Furthermore, tumoral ATXN3 suppression improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy. Importantly, ATXN3 expression was increased in human lung adenocarcinoma and melanoma, and its levels were positively correlated with PD-L1 as well as its transcription factors IRF1 and HIF-2α. Collectively, our study identifies what we believe to be a previously unknown deubiquitinase, ATXN3, as a positive regulator for PD-L1 transcription and provides a rationale for targeting ATXN3 to sensitize checkpoint blockade antitumor immunotherapy.

ATXN3 deubiquitinates YAP1 to promote tumor growth.

The ubiquitin-specific peptidase Ataxin-3 (ATXN3) has emerged as a potential oncogene in a variety of human cancers. However, the molecular mechanisms underlying how ATXN3 achieves its tumorigenic functions remain largely undefined. Herein, we report that targeted deletion of the ATXN3 gene in cancer cells by the CRISPR-Cas9 system resulted in decreased protein expression of Yes-associated protein 1 (YAP1) without altering its mRNA transcription. Interestingly, genetic ATXN3 suppression selectively inhibited the expression levels of YAP1 target genes including the connective tissue growth factor (Ctgf) and cysteine-rich angiogenic inducer 61 (Cyr61), both of which have important functions in cell adhesion, migration, proliferation and angiogenesis. Consequently, ATXN3 suppression resulted in reduced cancer cell growth and migration, which can also be largely rescued by YAP1 reconstitution. At the molecular level, ATNX3 interacts with the WW domains of YAP1 to protect YAP1 from ubiquitination-mediated degradation. Immunohistology analysis revealed a strong positive correlation between ATXN3 and YAP1 protein expression in human breast and pancreatic cancers. Collectively, our study defines ATXN3 as a previously unknown YAP1 deubiquitinase in tumorigenesis and provides a rationale for ATXN3 targeting in antitumor chemotherapy.

Interferon-induced transmembrane protein 3 in the hippocampus: a potential novel target for the therapeutic effects of recombinant human brain natriuretic peptide on sepsis-associated encephalopathy.

Objective: This study aims to explore whether interferon-induced transmembrane protein 3 (IFITM3) is involved in recombinant human brain natriuretic peptide (rhBNP)-mediated effects on sepsis-induced cognitive dysfunction in mice. Methods: The cellular localization and expression level of IFITM3 in the hippocampus were detected. The IFITM3 overexpression was achieved using an intracranial stereotactic system to inject an adeno-associated virus into the hippocampal CA1 region of mice. Field experiments, an elevated plus maze, and conditioned fear memory tests assessed the cognitive impairment in rhBNP-treated septic mice. Finally, in the hippocampus of septic mice, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining and Immunoblot were used to detect changes in the protein expression of cleaved Caspase-8 and cleaved Caspase-3 in apoptosis-related pathways, and toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) p65 in inflammatory pathways. Results: Fourteen days after cecal ligation and puncture (CLP) surgery, IFITM3 localized in the plasma membrane and cytoplasm of the astrocytes in the hippocampus of septic mice, partially attached to the perivascular and neuronal surfaces, but not expressed in the microglia. The expression of IFITM3 was increased in the astrocytes and neurons in the hippocampus of septic mice, which was selectively inhibited by the administration of rhBNP. Overexpression of IFITM3 resulted in elevated anxiety levels and long-term learning and memory dysfunction, completely abolished the therapeutic effect of rhBNP on cognitive impairment in septic mice, and induced an increase in the number of neuronal apoptosis in the hippocampal CA1 region. The expression levels of cleaved Caspase-3 and cleaved Caspase-8 proteins were significantly increased in the hippocampus, but the expression levels of TLR4 and NF-κB p65 were not increased. Conclusion: The activation of IFITM3 may be a potential new target for treating sepsis-associated encephalopathy (SAE), and it may be one of the key anti-apoptotic mechanisms in rhBNP exerting its therapeutic effect, providing new insight into the clinical treatment of SAE patients.

Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis.

Integrins plays critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription, which upregulation is involved in cancer stemness and metastasis. However, the molecular mechanisms underlying how integrins are upregulated in cancer stem cells (CSCs) remain as a biomedical mystery. Herein, we show that the death from cancer signature gene USP22 is essential to maintain the stemness of breast cancer cells through promoting the transcription of a group of integrin family members in particular integrin ß1 (ITGB1). Both genetic and pharmacological USP22 inhibition largely impaired breast cancer stem cell self-renewal and prevented their metastasis. Integrin ß1 reconstitution partially rescued USP22-null breast cancer stemness and their metastasis. At the molecular level, USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Importantly unbiased analysis of the TCGA database revealed a strong positive correlation between the death from cancer signature gene ubiquitin-specific peptidase 22 (USP22) and ITGB1, both of which are critical for cancer stemness, in more than 90% of human cancer types, implying that USP22 functions as a key factor to maintain stemness for a broad spectrum of human cancer types possibly through regulating ITGB1. To support this notion, immunohistochemistry staining detected a positive correlation among USP22, FoxM1 and integrin ß1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin ß1 signaling axis critical for cancer stemness and offers a potential target for antitumor therapy.

The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis.

P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.

scRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic cancer liver metastasis.

Invariant natural killer T (iNKT) cells are innate-like T cells that are abundant in liver sinusoids and play a critical role in tumor immunity. However, the role of iNKT cells in pancreatic cancer liver metastasis (PCLM) has not been fully explored. In this study, we employed a hemi-spleen pancreatic tumor cell injection mouse model of PCLM, a model that closely mimics clinical conditions in humans, to explore the role of iNKT cells in PCLM. Activation of iNKT cells with α-galactosylceramide (αGC) markedly increased immune cell infiltration and suppressed PCLM progression. Via single cell RNA sequencing (scRNA-seq) we profiled over 30,000 immune cells from normal liver and PCLM with or without αGC treatment and were able to characterize the global changes of the immune cells in the tumor microenvironment upon αGC treatment, identifying a total of 12 subpopulations. Upon treatment with αGC, scRNA-Seq and flow cytometry analyses revealed increased cytotoxic activity of iNKT/NK cells and skewing CD4 T cells towards a cytotoxic Th1 profile and CD8 T cells towards a cytotoxic profile, characterized by higher proliferation and reduced exhaustion marker PD1 expression. Moreover, αGC treatment excluded tumor associated macrophages. Lastly, imaging mass cytometry analysis uncovered the reduced epithelial to mesenchymal transition related markers and increased active CD4 and CD8 T cells in PCLM with αGC treatment. Overall, our findings uncover the protective function of activated iNKT cells in pancreatic cancer liver metastasis through increased NK and T cell immunity and decreased tumor associated macrophages.

Integrins in human hepatocellular carcinoma tumorigenesis and therapy.

ABSTRACT: Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin.

Iron homeostasis is critical for cellular and organismal function and is tightly regulated to prevent toxicity or anemia due to iron excess or deficiency, respectively. However, subcellular regulatory mechanisms of iron remain largely unexplored. Here, we report that SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) in hepatocytes controls systemic iron homeostasis in a ceruloplasmin (CP)-dependent, and ER stress-independent, manner. Mice with hepatocyte-specific Sel1L deficiency exhibit altered basal iron homeostasis and are sensitized to iron deficiency while resistant to iron overload. Proteomics screening for a factor linking ERAD deficiency to altered iron homeostasis identifies CP, a key ferroxidase involved in systemic iron distribution by catalyzing iron oxidation and efflux from tissues. Indeed, CP is highly unstable and a bona fide substrate of SEL1L-HRD1 ERAD. In the absence of ERAD, CP protein accumulates in the ER and is shunted to refolding, leading to elevated secretion. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD is responsible for the degradation of a subset of disease-causing CP mutants, thereby attenuating their pathogenicity. Together, this study uncovers the role of SEL1L-HRD1 ERAD in systemic iron homeostasis and provides insights into protein misfolding-associated proteotoxicity.

A deubiquitination module essential for Treg fitness in the tumor microenvironment.

The tumor microenvironment (TME) enhances regulatory T (Treg) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as Treg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying Treg fitness. We demonstrate that TME-specific stressors including transforming growth factor-ß (TGF-ß), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 (Usp22) and Usp21, by regulating TGF-ß, HIF, and mTOR signaling, respectively, to maintain Treg fitness. Simultaneous deletion of both USPs in Treg cells largely diminishes TME-induced Foxp3 up-regulation, alters Treg metabolic signatures, impairs Treg-suppressive function, and alleviates Treg suppression on cytotoxic CD8+ T cells. Furthermore, we developed the first Usp22-specific small-molecule inhibitor, which dramatically reduced intratumoral Treg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying Treg fitness and identify Usp22 as an antitumor therapeutic target that inhibits Treg adaptability in the TME.

SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer.

Endoplasmic reticulum (ER) homeostasis has been implicated in the pathogenesis of various forms of cancer; however, our understanding of the role of ER quality control mechanisms in tumorigenesis remains incomplete. Here, we show that the SEL1L-HRD1 complex of ER-associated degradation (ERAD) suppresses hepatocyte proliferation and tumorigenesis in mice. Hepatocyte-specific deletion of Sel1L or Hrd1 predisposed mice to diet/chemical-induced tumors. Proteomics screen from SEL1L-deficient livers revealed WNT5A, a tumor suppressor, as an ERAD substrate. Indeed, nascent WNT5A was misfolding prone and degraded by SEL1L-HRD1 ERAD in a quality control capacity. In the absence of ERAD, WNT5A misfolds is largely retained in the ER and forms high-molecular weight aggregates, thereby depicting a loss-of-function effect and attenuating WNT5A-mediated suppression of hepatocyte proliferation. In humans, SEL1L-HRD1 ERAD expression correlated positively with survival time for patients with liver cancer. Overall, our data reveal a key role of SEL1L-HRD1 ERAD in suppressing hepatocyte proliferation and liver cancer.

Hepatic Deletion of X-Box Binding Protein 1 in FXR Null Mice Leads to Enhanced Liver Injury.

FXR regulates bile acid metabolism, and FXR null (Fxr-/-) mice have elevated bile acid levels and progressive liver injury. The inositol-requiring enzyme 1α/X-box binding protein 1 (XBP1) pathway is a protective unfolded protein response pathway activated in response to endoplasmic reticulum stress. Here, we sought to determine the role of the inositol-requiring enzyme 1α/XBP1 pathway in hepatic bile acid toxicity using the Fxr-/- mouse model. Western blotting and quantitative PCR analysis demonstrated that hepatic XBP1 and other unfolded protein response pathways were activated in 24-week-old Fxr-/- compared with 10-week-old Fxr-/- mice but not in WT mice. To further determine the role of the liver XBP1 activation in older Fxr-/- mice, we generated mice with whole-body FXR and liver-specific XBP1 double KO (DKO, Fxr-/-Xbp1LKO) and Fxr-/-Xbp1fl/fl single KO (SKO) mice and characterized the role of hepatic XBP1 in cholestatic liver injury. Histologic staining demonstrated increased liver injury and fibrosis in DKO compared with SKO mice. RNA sequencing revealed increased gene expression in apoptosis, inflammation, and cell proliferation pathways in DKO mice. The proapoptotic C/EBP-homologous protein pathway and cell cycle marker cyclin D1 were also activated in DKO mice. Furthermore, we found that total hepatic bile acid levels were similar between the two genotypes. At age 60 weeks, all DKO mice and no SKO mice spontaneously developed liver tumors. In conclusion, the hepatic XBP1 pathway is activated in older Fxr-/- mice and has a protective role. The potential interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses.

Intratympanic steroid treatments rescued recurrent hearing loss following COVID-19 vaccination and detection of an intralabyrinthine schwannoma.

It remains unclear how to effectively treat rare cases of sudden and recurrent hearing losses which might coincidently follow vaccination. We report the first case, to our knowledge, of systemic and local steroid administration to successfully treat sudden and recurrent left-ear hearing loss, respectively, following a second dose of the BNT162b2 COVID-19 mRNA vaccination which inflammatory response potentially affected an existing left intralabyrinthine schwannoma in a young male patient. This case highlights the importance and timing of intratympanic steroid treatment strategies to suppress the progressive symptoms and restore hearing to a stable condition, and therefore avoid permanent hearing loss which would otherwise demand a surgical removal of the schwannoma to improve vertigo and reconstitute artificial hearing.

NAC1 modulates autoimmunity by suppressing regulatory T cell-mediated tolerance.

We report here that nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the Broad-complex, Tramtrack, Bric-a-brac/poxvirus and zinc finger (BTB/POZ) gene family, is a negative regulator of FoxP3 in regulatory T cells (Tregs) and a critical determinant of immune tolerance. Phenotypically, NAC1-/- mice showed substantial tolerance to the induction of autoimmunity and generated a larger amount of CD4+ Tregs that exhibit a higher metabolic profile and immune-suppressive activity, increased acetylation and expression of FoxP3, and slower turnover of this transcription factor. Treatment of Tregs with the proinflammatory cytokines interleukin-1ß or tumor necrosis factor-α induced a robust up-regulation of NAC1 but evident down-regulation of FoxP3 as well as the acetylated FoxP3. These findings imply that NAC1 acts as a trigger of the immune response through destabilization of Tregs and suppression of tolerance induction, and targeting of NAC1 warrants further exploration as a potential tolerogenic strategy for treatment of autoimmune disorders.

A systematic review of pharmacologic treatment efficacy for depression in older patients with cancer.

Background: Older adults ≥65 years of age represent the majority of new cancer diagnoses and are vulnerable to developing depression-like symptoms. Evaluation and management of depression in older cancer patients is underappreciated despite its high prevalence and impact on health-related quality of life. Although antidepressants are the primary pharmacologics used to treat depressive-like symptoms, the efficacy and overall benefit(s) are not well-characterized in older adult patients with cancer. The objective of this investigation was to review what is known about the efficacy of pharmacologic treatment for older adults with depression and cancer. Methods: PubMed (Medline) and EMBASE (Elsevier) databases were analyzed for relevant literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: 1,919 unique studies were identified for title and abstract screening. Forty-eight publications were retrieved for full review. None of the identified studies evaluated the potential for benefit after pharmacological treatment among older adults with cancer and depression. Twenty-seven publications met all study criteria except for an analysis focused on older patients. Conclusion: We discovered a universal absence of literature with a relevance to pharmacologic antidepressant treatment effects in older adult patients with cancer. This included a lack of evaluation in patients with brain tumors who have an unusually high predilection for developing depression. Our findings suggest that new research is critically needed for understanding optimal clinical management strategies in older adults with cancer and depression who are treated with antidepressants.