Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Exosomal noncoding RNA-mediated spatiotemporal regulation of lipid metabolism: Implications in immune evasion and chronic inflammation.

The hallmark of chronic inflammatory diseases is immune evasion. Successful immune evasion involves numerous mechanisms to suppress both adaptive and innate immune responses. Either direct contact between cells or paracrine signaling triggers these responses. Exosomes are critical drivers of these interactions and exhibit both immunogenic and immune evasion properties during the development and progression of various chronic inflammatory diseases. Exosomes carry diverse molecular cargo, including lipids, proteins, and RNAs that are crucial for immunomodulation. Moreover, recent studies have revealed that exosomes and their cargo-loaded molecules are extensively involved in lipid remodeling and metabolism during immune surveillance and disease. Many studies have also shown the involvement of lipids in controlling immune cell activities and their crucial upstream functions in regulating inflammasome activation, suggesting that any perturbation in lipid metabolism results in abnormal immune responses. Strikingly, the expanded immunometabolic reprogramming capacities of exosomes and their contents provided insights into the novel mechanisms behind the prophylaxis of inflammatory diseases. By summarizing the tremendous therapeutic potential of exosomes, this review emphasizes the role of exosome-derived noncoding RNAs in regulating immune responses through the modulation of lipid metabolism and their promising therapeutic applications.

Prognostic potential of METTL3 expression in patients with gastric cancer.

Methyltransferase-like 3 (METTL3) is a crucial component of the m6A methyltransferase complex, which serves pivotal roles in tumor progression. The present study investigated the prognostic significance of METTL3 expression in gastric cancer (GC). The expression levels of METTL3 were assessed by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) tissue specimens from 158 patients with GC. Propensity score matching (PSM) analysis was performed to clarify its prognostic potential. METTL3 gene expression was also investigated in fresh frozen specimens from another independent cohort of 57 patients with GC to establish its clinical relevance. Knockdown of METTL3 by small interfering RNA transfection was performed to evaluate its function in vitro. METTL3 expression was significantly higher in cancerous tissues compared with in corresponding normal mucosa (P<0.0001), and high METTL3 expression was an independent prognostic factor for overall and disease-free survival in the FFPE cohort of patients with GC. PSM analysis revealed that elevated METTL3 expression was significantly associated with poor survival outcomes, which was subsequently validated in another cohort of fresh frozen specimens. Knockdown of METTL3 inhibited proliferation, invasion, migration and anoikis resistance in GC cells. In conclusion, METTL3 expression may be used as a clinically feasible prognostic marker and could serve as a potential therapeutic target in patients with GC.

LncRNAs associated with glioblastoma: From transcriptional noise to novel regulators with a promising role in therapeutics.

Glioblastoma multiforme (GBM) is the most widespread and aggressive subtype of glioma in adult patients. Numerous long non-coding RNAs (lncRNAs) are deregulated or differentially expressed in GBM. These lncRNAs possess unique regulatory functions in GBM cells, ranging from high invasion/migration to recurrence. This review outlines the present status of specific involvement of lncRNAs in GBM pathogenesis, with a focus on their association with key molecular and cellular regulatory mechanisms. Also, we highlighted the potential of different novel RNA-based strategies that may be beneficial for therapeutic purposes.

Unraveling the Role of Innate Lymphoid Cells in AcuteMyeloid Leukemia.

Over the past 50 years, few therapeutic advances have been made in treating acute myeloid leukemia (AML), an aggressive form of blood cancer, despite vast improvements in our ability to classify the disease. Emerging evidence suggests the immune system is important in controlling AML progression and in determining prognosis. Natural killer (NK) cells are important cytotoxic effector cells of the innate lymphoid cell (ILC) family that have been shown to have potent anti-leukemic functions. Recent studies are now revealing impairment or dysregulation of other ILCs in various types of cancers, including AML, which limits the effectiveness of NK cells in controlling cancer progression. NK cell development and function are inhibited in AML patients, which results in worse clinical outcomes; however, the specific roles of other ILC populations in AML are just now beginning to be unraveled. In this review, we summarize what is known about the role of ILC populations in AML.

The pleiotropic role of transcription factor STAT3 in oncogenesis and its targeting through natural products for cancer prevention and therapy.

Signal transducer and activator of transcription 3 (STAT3) is one of the crucial transcription factors, responsible for regulating cellular proliferation, cellular differentiation, migration, programmed cell death, inflammatory response, angiogenesis, and immune activation. In this review, we have discussed the classical regulation of STAT3 via diverse growth factors, cytokines, G-protein-coupled receptors, as well as toll-like receptors. We have also highlighted the potential role of noncoding RNAs in regulating STAT3 signaling. However, the deregulation of STAT3 signaling has been found to be associated with the initiation and progression of both solid and hematological malignancies. Additionally, hyperactivation of STAT3 signaling can maintain the cancer stem cell phenotype by modulating the tumor microenvironment, cellular metabolism, and immune responses to favor drug resistance and metastasis. Finally, we have also discussed several plausible ways to target oncogenic STAT3 signaling using various small molecules derived from natural products.