Tumor Research Articles

Development of a recombinant human IgG1 monoclonal antibody against the TRBV5-1 segment of the T cell receptor for the treatment of mature T cell neoplasms

BackgroundMature T-cell neoplasms arise from the neoplastic transformation of a single T lymphocyte, and all cells in a neoplastic clone share the same V segment in the beta chain of the T-cell receptor (TCR). These segments may represent an innovative target for the development of targeted therapies.MethodsA specific V segment of the TCR beta chain (TRBV5-1) was analyzed using bioinformatic tools, identifying three potential antigenic peptides. One of these peptides, selected for synthesis, was used to screen a library of human single-chain variable fragments (scFv) through phage display. One fragment demonstrated high affinity and specificity for the antigen and was used to produce a human monoclonal antibody of the IgG1 class.ResultsSurface plasmon resonance (SPR) studies confirmed the high affinity of the monoclonal antibody for the antigen in the nanomolar range. Flow cytometry analysis on patients’ samples demonstrated that the antibody, conjugated with a fluorochrome, selectively binds to tumor T lymphocytes expressing TRBV5-1, without binding to other lymphocytes or blood cell components.ConclusionsThe development of fully human IgG1 monoclonal antibodies targeting specific V segments of the TCR beta chain represents a potential therapeutic option for patients with mature T-cell neoplasms.

Impact of T Cell Exhaustion and Stroma Senescence on Tumor Cell Biology and Clinical Outcome of Head and Neck Squamous Cell Carcinomas

Head and neck squamous cell carcinomas (HNSCC) have an overall poor prognosis, especially in locally advanced and metastatic stages. In most cases, multimodal therapeutic approaches are required and show only limited cure rates with a high risk of tumor recurrence. Anti-PD-1 antibody treatment was recently approved for recurrent and metastatic cases but to date, response rates remain lower than 25%. Therefore, the investigation of the immunological tumor microenvironment and the identification of novel immunotherapeutic targets in HNSCC is of paramount importance. In our study, we used tissue samples of n = 116 HNSCC patients for the immunohistochemical detection of the intratumoral and peritumoral expression of T cell exhaustion markers (PD-1, LAG-3, TIM-3) on tumor infiltration leukocytes (TIL), as well as the expression level of stromal senescence markers (IL-8, MMP-3) on tumor-associated fibroblasts. The clinical parameter of the vitamin D serum status as well as the histopathological HPV infection status of the tumor was correlated with the expression rates of the biomarkers and the overall patient survival. An increased peritumoral and intratumoral expression of the biomarkers PD-1 and TIM-3 significantly correlated with improved overall patient survival. A high peritumoral expression of LAG-3 correlated with better overall survival. A positive HPV tumor status correlated with a significantly elevated expression of PD-1 and TIM-3. Biomarkers of stromal senescence showed no influence on the patient outcome. However, the vitamin D serum status showed no influence on patient outcomes or biomarker expressions. Our study identified PD-1, LAG-3, and TIM-3 as promising targets of a therapeutic strategy targeting the tumor microenvironment in HNSCC, particularly among HPV-positive patients, where a higher expression of these checkpoints correlated with an improved overall survival. These findings support the potential of antibodies targeting these immune checkpoints to enhance treatment efficacy, especially in the context of bispecific targeting.

HDACi combination therapy with IDO1i remodels the tumor microenvironment and boosts antitumor efficacy in colorectal cancer with microsatellite stability

BackgroundImmunotherapy for colorectal cancer (CRC) with microsatellite stability (MSS) and mismatch repair proficiency (pMMR) has shown limited success in clinical trials. The combination of immunomodulators and immune checkpoint inhibitors (ICIs) is a potential strategy for treating CRC.MethodsHistone deacetylase (HDAC) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in CRC tissues and adjacent normal tissues was analyzed via database analysis, immunohistochemistry, and western blotting. A nanodrug designated as NP-I/P was subsequently formulated, encapsulating an IDO1 inhibitor (IDO1i; namely, epacadostat) and an immunomodulatory HDAC inhibitor (HDACi; namely, panobinostat). The antitumor efficacy of the nanoparticles and their effects on tumor microenvironment features were evaluated via in vitro and in vivo experiments.ResultsIn the present study, we found that HDAC overexpression and IDO1 expression were attenuated in MSS/pMMR CRC. Thus, a nanodrug designated as NP-I/P was formulated to encapsulate epacadostat and panobinostat. In vitro, NP-I/P treatment promoted the apoptosis of tumor cells and induced the release of damage-associated molecular patterns, thereby leading to cell death–associated immune activation. The in vivo results revealed that NP-I/P treatment reversed the immunosuppressive phenotype of the microenvironment by inducing tumor immunogenic cell death (ICD), promoting CD8+ T cell infiltration, and reducing the numbers of Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells. Finally, the results of the patient-derived xenograft and patient-derived organoid models demonstrated that NP-I/P treatment triggered tumor cell death and modulated the immune microenvironment in human CRC.ConclusionThe combination of IDO1 and HDAC inhibitors represents a promising strategy for CRC treatment, and NP-I/P is a candidate for clinical trials.

A Catch-Release Strategy for the Genomics-Driven Discovery of Antiproliferative Furan-Functionalized Peptides.

Furan-functionalized peptides are of significant pharmacological interest due to their pronounced bioactivities and unique potential for orthogonal bioconjugation and derivatization. However, naturally occurring peptides with furyl side chains are exceedingly rare. This study presents a streamlined method to predict and assess the microbial production of peptides incorporating 3-furylalanine (Fua) moieties. The approach integrates genome mining and the reversible, chemoselective tagging of furyl residues, utilizing their unique Diels-Alder reactivity, for mass spectrometry-guided identification of candidate compounds. By employing the rhizonin Fua synthase as a bioinformatic handle and through heterologous reconstitution of Fua biosynthesis, we identified previously unknown Fua biosynthetic pathways in diverse bacterial phyla, including actinomycetes, cyanobacteria, actinobacteria, and g-proteobacteria, suggesting that Fua-containing peptides are remarkably widely distributed. Metabolic profiling by reversible tagging facilitated the detection of native Fua-containing metabolites. The successful adaptation of this method for solid support enabled the direct enrichment of furyl-substituted peptides from complex mixtures. This multi-pronged approach enabled the discovery and characterization of two novel families of Fua cyclopeptides (rubriamides and typhamides) with potent antiproliferative effects against human tumor cells and nematodes. The innovative catch-and-release strategy, in conjunction with genome mining, represents a valuable tool for the discovery of new furan-substituted natural products.

Spatiotemporal Mapping of Lymphatic Metastases in Gastric Cancer Using Tumor-Trackable and Enzyme-Activatable Near-Infrared Fluorescent Nanoprobes.

Sentinel lymph node biopsy holds significant importance in cancer management, yet the challenge persists in early detection and precise resection of metastasis lymph nodes (LNs) due to the absence of specific and sensitive optical probes. This study reports metastatic LN reporters (MLRs) with an activatable optical output for accurate spatiotemporal mapping of lymphatic metastases in gastric cancer. MLRs are self-assembled entities incorporating mixed amphiphiles with a lipophilic tail and a tumor-targeting ligand or a fluorescent moiety that is caged with a switch cleavable by tumor-specific β-galactosidase (β-Gal). After draining into LNs, MLRs selectively activate their near-infrared fluorescence in the presence of spreading tumor cells. In orthotopic gastric cancer mouse models, the representative reporter MLR1 distinguishes macro/micrometastatic LNs from benign LNs and enables early detection of skip LNs metastasis patterns in a spatial-dependent manner. Such an active sensing mechanism provides a high level of sensitivity and specificity comparable to those of flow cytometry analysis. In surgically resected patient specimens, MLR1 differentiates cancerous tissues and metastatic LNs from normal tissues and benign LNs within 1 h. This study thus presents NIRF nanoprobes that permit facile detection of LN metastases in GC patient samples and highlights a generic translatable nanoprobe design for understanding metastatic progression.

Rotenone, Rhodamine 123 and Janus Green Induce Damage to Nuclear DNA in Ascites Tumor Cells from Mice, Rotenone and Rhodamine in X-Irradiated Cells Contribute to the Maintenance of Genome Integrity

Rotenone, Rhodamine 123 and Janus Green Induce Damage to Nuclear DNA in Ascites Tumor Cells from Mice, Rotenone and Rhodamine in X-Irradiated Cells Contribute to the Maintenance of Genome Integrity

Engineering a Near-Infrared Spiro-Based Aggregation-Induced Emission Luminogen for DNAzyme-Sensitized Photothermal Therapy with High Efficiency and Accuracy.

Aggregation-induced emission luminogen (AIEgens)-based photothermal therapy (PTT) has grown into a sparkling frontier for tumor ablation. However, challenges remain due to the uncoordinated photoluminescence (PL) and photothermal properties of classical AIEgens, along with hyperthermia-induced antiapoptotic responses in tumor cells, hindering satisfactory therapeutic outcomes. Herein, a near-infrared (NIR) spiro-AIEgen TTQ-SA was designed for boosted PTT by auxiliary DNAzyme-regulated tumor cell sensitization. TTQ-SA with a unique molecular structure and packing mode was initially fabricated, endowing it with a strong AIE effect, favorable PL quantum yield, and good photothermal performance. DNAzyme, as a gene silencing tool, could alleviate antiapoptosis response during PTT. By integrating TTQ-SA and DNAzyme into folate-modified poly(lactic-co-glycolic acid) (PLGA) polymer, the as-fabricated nanosystem could promote cell apoptosis and sensitize tumor cells to PTT, thereby maximizing the therapeutic outcomes. With the combination of spiro-AIEgen-based PTT and DNAzyme-based gene silencing, the as-designed nanosystem showed promising NIR and photothermal imaging abilities for tumor targeting and demonstrated significant cell apoptotic, antitumor, and antimetastasis effects against orthotopic breast cancer. Furthermore, a synergistic antitumor effect was realized in spontaneous MMTV-PyMT transgenic mice. These findings offer new insights into AIEgen-based photothermal theranostics and DNAzyme-regulated tumor cell sensitization, paving the way for synergistic gene silencing-PTT nanoplatforms in clinical research.

Antiproliferative Activity and Molecular Docking Analyses of Sesquiterpene Lactones Obtained from Activity-Directed Isolation of Centaurea saligna (K.Koch) Wagenitzin Neoplastic Cells.

Secondary metabolites obtained from plants are among the most commonly encountered chemotherapeutics used in cancer treatment. Plants contain thousands of metabolites; therefore, it is important to reach the compound primarily responsible for activity by fractionating plant extracts through activity-guided isolation. The cytotoxic activities of C. saligna fractions, sub-fractions, and all pure compounds obtained from the plant were investigated in vitro using MCF-7 (human breast cancer), HeLa (human cervical cancer), and PC-3 (prostate cancer) cell lines. Eighteen compounds were isolated from C. saligna, comprising eight sesquiterpene lactones, three flavonoids, five lignans, and two phenolic compounds, with their structures elucidated through 1H-NMR, 13C-NMR, and HMBC spectroscopic techniques. The molecular docking scores of the pure compounds obtained from these sub-fractions were determined using both AutoDock and AutoDock Vina programs. It has been proven that the affinities of linichlorin B and aguerin B for Bcl-2 are higher than those of other compounds, considering the calculated Ki values and placement scores. Notable activities of linichlorin B, cynaropicrin, and aguerin B (with IC50 values of 13.67μg/ml, 6.79μg/ml, and 3.46μg/ml, respectively) were detected in the PC-3 cell line; aguerin B demonstrated activity most comparable to the standard anticancer agent doxorubicin. Likewise, linichlorin B, aguerin B, and cynaropicrin demonstrated notable efficacy in the HeLa and MCF-7 cell lines, as reported by the American National Cancer Institute. Aguerin B, linichlorin B, and cynaropicrin are projected to serve as promising novel chemotherapeutic agents for cancer therapy.

Soluble TREM2 drives triple-negative breast cancer progression via activation of the AKT pathway.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a key role in immune regulation, particularly within tumor-associated macrophages (TAMs). In triple-negative breast cancer (TNBC), TREM2+ TAMs have been shown to modulate the tumor microenvironment, but the role of its soluble form: soluble triggering receptor expressed on myeloid cells 2 (sTREM2), produced through proteolytic cleavage, remains unclear. In this study, we investigated the effects of sTREM2 on TNBC progression. In vitro, treatment of TNBC cells with recombinant sTREM2 or sTREM2-containing culture supernatant significantly enhanced cell proliferation, invasion, and migration. These effects were further confirmed by the use of TREM2-neutralizing antibodies, which abrogated sTREM2's tumor-promoting activities. In vivo, peri-tumoral injections of recombinant sTREM2 led to a notable acceleration of tumor growth in mouse models. Mechanistically, we found that the effects of sTREM2 were mediated through its binding to the TG2 protein in 4T1 cells, thereby activating the AKT signaling pathway. Collectively, our findings suggest that sTREM2 drives TNBC progression by enhancing critical tumor cell functions, positioning it as a potential therapeutic target for TNBC treatment.

Synergistic Target-Attacking Tumor Cells and M2 Macrophages via a Triple-Responsive Nanoassembly for Complete Metastasis Blocking.

Collaboration of cancerous cells and microenvironment is the root for tumor spreading, leading to difficulty in complete metastasis blockage via mono-intervention. Herein, a triple-responsive nanoassembly is designed for orienting tumor cells and migration-driving M2 tumor associated macrophages (TAMs) in microenvironment for efficient anti-metastatic therapy. Structurally, a reactive oxygen species (ROS)-responsive crosslinked short-chain polyquaternium is synthesized to bridge graphene oxide (GO) scaffold with apolipoprotein A-I crown via borate-crosslinking, electrostatic adherence, and coordinative coupling. The protein-crowning polymeric GO nanoparticles could give multimodal shielding and triple-responsive release of doxorubicin and Snail-targeted siRNA. Tailor-made apolipoprotein A-I crown fulfills nanoparticles synergistically attacking tumor cells and M2 TAMs via binding with overexpressed scavenger receptors. The findings witness the targeted accumulation and potent cytotoxicity of the hybrid nanoparticles for M2 TAMs and tumor cells; especially, elimination of M2 TAMs in tumor microenvironment holds back Snail-enhancing transforming growth factor (TGF)-β signal pathway, which collaborates with Snail silencing in tumor cells to reverse epithelial mesenchymal transition (EMT) and metastasis-promoting niche. Collectively, the synergistic targeting therapeutic platform could provide a promising solution for metastatic tumor treatment.

TLS and immune cell profiling: immunomodulatory effects of immunochemotherapy on tumor microenvironment in resectable stage III NSCLC

BackgroundThe use of programmed death-1 (PD-1) inhibitors in the neoadjuvant setting for patients with resectable stage III NSCLC has revolutionized this field in recent years. However, there is still 40%-60% of patients do not benefit from this approach. The complex interactions between immune cell subtypes and tertiary lymphoid structures (TLSs) within the tumor microenvironment (TME) may influence prognosis and the response to immunochemotherapy. This study aims to assess the relationship between immune cells subtypes and TLSs to better understand their impact on immunotherapy response.MethodsThis study initially compared the tertiary lymphoid structures (TLSs) density among patients who underwent immunochemotherapy, chemotherapy and upfront surgery using 123 tumor samples from stage-matched patients. Multiplex immunohistochemistry (mIHC) was employed to analyze the spatial distribution of PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs. Cytometry by time-of-flight (CyTOF) was used to assess immune cell dynamics in paired biopsy and resection specimens from six patients who underwent immunochemotherapy. Key immune cells were validated in newly collected samples using flow cytometry, mIHC, and in vitro CAR-T cells model.ResultsPatients who underwent neoadjuvant chemotherapy or immunochemotherapy exhibited increased TLSs compared to those who opted for upfront surgery. The TLS area-to-tumor area ratio distinguished pCR+MPR and NR patients in the immunochemotherapy group. Spatial analysis revealed variations in the distance between PD-L1+CD11c+ cells and PD1+CD8+ T cells within TLSs in the immunochemotherapy group. CyTOF analysis revealed an increase in the frequency of key immune cells (CCR7+CD127+CD69+CD4+ and CD38+CD8+ cells) following combined therapy. Treatment responders exhibited an increase in CCR7+CD4+ T cells, whereas CD38+CD8+ T cells were associated with compromised treatment effectiveness.ConclusionsImmunochemotherapy and chemotherapy increase TLSs and granzyme B+ CD8+ T cells in tumors. The TLS area-to-tumor ratio distinguishes responders from non-responders, with PD-L1+ dendritic cells near CD8+PD-1+ T cells linked to efficacy, suggesting that PD-1 inhibitors disrupt harmful interactions. Post-immunochemotherapy, CD8+ T cells increase, but CD38+CD8+ T cells show reduced functionality. These findings highlight the complex immune dynamics and their implications for NSCLC treatment.

Nanozyme as Tumor Energy Homeostasis Disruptor to Augment Cascade Catalytic Therapy.

Breaking the balance of the tumor microenvironment and reshaping it sustainably remain major challenges in lung cancer treatment. Here, a "tumor energy homeostasis disruptor", the Cu2O@Au nanozyme was developed, which exhibits excellent glucose oxidase-like activity, enabling it to be used for starvation therapy and as a mimic peroxidase for chemodynamic therapy (CDT), producing •OH. Cu2O@Au nanozymes consume glucose at the tumor site to block the tumor's energy supply, produce H2O2 continuously, and lower the pH to enhance the efficiency of CDT, initiating a cascade reaction that leads to a storm of reactive oxygen species (ROS). Furthermore, Cu2O@Au nanozyme consumes glutathione and reduces the expression of the SLC7A11 (xCT) protein to decrease cancer cell uptake of cysteine, further enhancing the burst of ROS, resulting in lipid peroxidation in tumor cells and ultimately leading to ferroptosis. The excellent photothermal performance of Cu2O@Au can further enhance CDT. Additionally, Cu2O@Au nanozyme also has computed tomography (CT) and photothermal imaging capabilities. In conclusion, Cu2O@Au nanozymes, acting as tumor energy homeostasis disruptor, can effectively inhibit tumor growth and successfully achieve the synergistic effects of starvation therapy/CDT/photothermal therapy (PTT). This multifunctional nanozyme holds promise for providing valuable insights and therapeutic strategies for cancer treatment.

Epitranscriptomic RNA m6A Modification in Cancer Therapy Resistance: Challenges and Unrealized Opportunities.

Significant advances in the development of new cancer therapies have given rise to multiple novel therapeutic options in chemotherapy, radiotherapy, immunotherapy, and targeted therapies. Although the development of resistance is often reported along with temporary disease remission, there is often tumor recurrence of an even more aggressive nature. Resistance to currently available anticancer drugs results in poor overall and disease-free survival rates for cancer patients. There are multiple mechanisms through which tumor cells develop resistance to therapeutic agents. To date, efforts to overcome resistance have only achieved limited success. Epitranscriptomics, especially related to m6A RNA modification dysregulation in cancer, is an emerging mechanism for cancer therapy resistance. Here, recent studies regarding the contributions of m6A modification and its regulatory proteins to the development of resistance to different cancer therapies are comprehensively reviewed. The promise and potential limitations of targeting these entities to overcome resistance to various anticancer therapies are also discussed.

Tumor-Expressed SPPL3 Supports Innate Antitumor Immune Responses.

The development of an effective antitumor response relies on the synergistic actions of various immune cells that recognize tumor cells via distinct receptors. Tumors, however, often manipulate receptor-ligand interactions to evade recognition by the immune system. Recently, we highlighted the role of neolacto-series glycosphingolipids (nsGSLs), produced by the enzyme β1,3-N-acetylglucosaminyltransferase 5 (B3GNT5), in tumor immune escape. We previously demonstrated that loss of signal peptide peptidase like 3 (SPPL3), an inhibitor of B3GNT5, results in elevated levels of nsGSLs and impairs CD8 T cell activation. The impact of loss of SPPL3 and an elevated nsGSL profile in tumor cells on innate immune recognition remains to be elucidated. This study investigates the antitumor efficacy of neutrophils, NK cells, and γδ T cells on tumor cells lacking SPPL3. Our findings demonstrate that SPPL3-deficient target cells are less susceptible to trogocytosis by neutrophils and killing by NK cells and γδ T cells. Mechanistically, SPPL3 influences trogocytosis and γδ T cell-instigated killing through modulation of nsGSL expression, whereas SPPL3-mediated reduced killing by NK cells is nsGSL-independent. The nsGSL-dependent SPPL3 sensitivity depends on the proximity of surface receptor domains to the cell membrane and the affinity of receptor-ligand interactions as shown with various sets of defined antibodies. Thus, SPPL3 expression by tumor cells alters crosstalk with immune cells through the receptor-ligand interactome thereby driving escape not only from adaptive but also from innate immunity. These data underline the importance of investigating a potential synergism of GSL synthesis inhibitors with current immune cell-activating immunotherapies.

Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma.

Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via "subcutaneous" and "orthotopic" HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.

Role of circulating tumor cells in breast cancer.

Circulating tumor cells (CTCs) are tumor cells that shed from the primary tumor or metastatic loci, intravasate, and circulate in the bloodstream. CTCs have been suggested to play a major role in the metastatic spread of cancer, constantly shedding from tumors during proliferation or as a result of mechanical insults. Breast cancer (BC) is one of the most representative tumors in CTC research, with several studies conducted on its clinical validity and utility in both early and advanced BC (EBC and ABC, respectively). The assessment of the number and molecular profiles of CTCs is expected to provide a more tailored therapy for patients with BC. The detection of CTCs is usually dependent on molecular markers, and epithelial cell adhesion molecules are widely used. Although the CellSearch® technology has been widely utilized for CTC detection, recent advances have led to the development of novel detection methods, facilitating further molecular analysis. In this review, we discuss the clinical applications of CTCs, current status of research, and efforts to incorporate CTC analysis into clinical practice. Additionally, we discuss potential challenges and future directions for integrating CTC analysis into clinical practice.

Immune Checkpoint Inhibitor Myopathy: The Double-Edged Sword of Cancer Immunotherapy.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several malignancies, with improved survival. These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Releasing the brakes on the immune system has consequences, however, in the form of immune-related adverse events (irAEs), which may affect any organ. Neurologic irAEs represent 1%-3% of all irAEs, with immune-mediated myopathy (ICI myopathy) being the most common manifestation. Recent large patient series and systematic reviews have established the key features and highlighted new insights into ICI myopathy. ICI myopathy is characterized by an acute or subacute onset of oculobulbar and/or proximal limb weakness, with or without associated respiratory insufficiency and myocarditis. Creatine kinase elevation is common. Oculobulbar presentations with or without respiratory failure may be misattributed to neuromuscular junction disorders, particularly because acetylcholine receptor antibodies are present in up to 40% of patients; however, an electrodiagnostic evidence of a defect of neuromuscular transmission is often absent even in patients with severe weakness, highlighting that the myopathic process is the driving force behind these presentations. Muscle histopathology commonly demonstrates a unique signature of multifocal clusters of necrotic and regenerating fibers, differentiating ICI myopathy from other autoimmune myopathies. Transcriptomic analysis has uncovered distinct subgroups within ICI myopathy, revealing varying degrees of type 1 and type 2 interferon pathway activation alongside notable upregulation of the interleukin (IL)-6 pathway in affected muscle tissue. This discovery presents a promising avenue for intervention through the use of therapies that suppress the interferon pathway and target IL-6 or its receptor. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

Multi-omic profiling highlights factors associated with resistance to immuno-chemotherapy in non-small-cell lung cancer.

Although immune checkpoint blockade (ICB) therapies have shifted the treatment paradigm for non-small-cell lung cancer (NSCLC), many patients remain resistant. Here we characterize the tumor cell states and spatial cellular compositions of the NSCLC tumor microenvironment (TME) by analyzing single-cell transcriptomes of 232,080 cells and spatially resolved transcriptomes of tumors from 19 patients before and after ICB-chemotherapy. We find that tumor cells and secreted phosphoprotein 1-positive macrophages interact with collagen type XI alpha 1 chain-positive cancer-associated fibroblasts to stimulate the deposition and entanglement of collagen fibers at tumor boundaries, obstructing T cell infiltration and leading to poor prognosis. We also reveal distinct states of tertiary lymphoid structures (TLSs) in the TME. Activated TLSs are associated with improved prognosis, whereas a hypoxic microenvironment appears to suppress TLS development and is associated with poor prognosis. Our study provides novel insights into different cellular and molecular components corresponding to NSCLC ICB-chemotherapeutic responsiveness, which will benefit future individualized immuno-chemotherapy.

Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic.

Our research aims to understand the adaptive, ergo potentially metastatic, responses of prostate cancer to changing microenvironments. Emerging evidence implicates a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study revealed that PACC presence in patient prostate tumors at the time of radical prostatectomy was predictive of future metastasis. To test for a causative relationship between PACC state biology and metastasis in prostate cancer, we leveraged a novel method designed for flow-cytometric detection of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) from animal models. This approach provides both quantitative and qualitative information about the number and PACC-status of recovered CTCs and DTCs. Specifically, we applied this approach to analysis of subcutaneous, caudal artery, and intracardiac murine models. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state. Furthermore, in vivo colonization assays proved PACC populations can regain proliferative capacity at metastatic sites. Additional in vitro analyses revealed a PACC-specific partial Epithelial-to-Mesenchymal-Transition phenotype and a pro-metastatic secretory profile, together providing preliminary evidence of pro-metastatic mechanisms specific to the PACC state. Implications: Considering that many anti-cancer agents induce the PACC state, our data positions the increased metastatic competency of PACC state cells as an important unforeseen ramification of neoadjuvant regimens, which may help explain clinical correlations between chemotherapy and metastatic progression.

Novel Flavin Mononucleotide-Functionalized Cerium Fluoride Nanoparticles for Selective Enhanced X-Ray-Induced Photodynamic Therapy

X-ray-induced photodynamic therapy (X-PDT) represents a promising new method of cancer treatment. A novel type of nanoscintillator based on cerium fluoride (CeF3) nanoparticles (NPs) modified with flavin mononucleotide (FMN) has been proposed. A method for synthesizing CeF3-FMN NPs has been developed, enabling the production of colloidal, spherical NPs with an approximate diameter of 100 nm, low polydispersity, and a high fluorescence quantum yield of 0.42. It has been demonstrated that CeF3-FMN NPs exhibit pH-dependent radiation-induced redox activity when exposed to X-rays. This activity results in the generation of reactive oxygen species, which is associated with the scintillation properties of cerium and the transfer of electrons to FMN. The synthesized NPs have been demonstrated to exhibit minimal cytotoxicity towards normal cells (NCTC L929 fibroblasts) but are more toxic to tumor cells (epidermoid carcinoma A431). Concurrently, the synthesized NPs (CeF3 and CeF3-FMN NPs) demonstrate a pronounced selective radiosensitizing effect on tumor cells at concentrations of 10−7 and 10−3 M, resulting in a significant reduction in their clonogenic activity, increasing radiosensitivity for cancer cells by 1.9 times following X-ray irradiation at a dose of 3 to 6 Gy. In the context of normal cells, these nanoparticles serve the function of antioxidants, maintaining a high level of clonogenic activity. Functional nanoscintillators on the basis of cerium fluoride can be used as part of the latest technologies for the treatment of tumors within the framework of X-PDT.