Average log change rate of pretreatment squamous cell carcinoma antigen after concurrent chemoradiotherapy in stage IIIC1 cervical squamous cell carcinoma.

We aimed to determine whether pretreatment squamous cell carcinoma antigen (SCC-Ag) levels and the average logarithmic change in SCC-Ag levels ( Δ log SCC-Ag Δ time ) after concurrent chemoradiotherapy (CCRT) could predict treatment outcomes in patients with stage IIIC1 cervical squamous cell carcinoma (SCC). We analyzed 168 patients with stage IIIC1 cervical SCC who underwent primary CCRT and collected data on age, local extension, treatment details, hematological parameters, and tumor markers such as SCC-Ag and carcinoembryonic antigen 21-1 (Cyfra). Predictive performances of pretreatment SCC-Ag levels and Δ log SCC-Ag Δ time were assessed using receiver operating characteristic curves. Survival analysis was performed using the Cox regression model and Kaplan-Meier plots. The combination of pretreatment SCC-Ag levels and Δ log SCC-Ag Δ time showed higher area under the curve values than pretreatment SCC-Ag levels alone (area under the curve; 95% confidence interval [CI] 0.708 [0.581-0.836] vs. 0.666 [0.528-0.804], respectively). Pretreatment SCC-Ag (≥ 5 ng/ml and Cyfra levels (≥ 3.15 ng/ml) and Δ log SCC-Ag Δ time (≥ - 1.575) were significant predictors of disease-specific survival. The 5-year disease-specific survival rates significantly differed among the low-, intermediate-, and high-risk groups. Risk stratification using both pretreatment SCC-Ag levels and Δ log SCC-Ag Δ time may predict treatment outcomes of patients with stage IIIC1 SCC.

K48-linked deubiquitination of VGLL4 by USP15 enhances the efficacy of tumor immunotherapy in triple-negative breast cancer.

Immunotherapy based on PD-1/PD-L1 antagonists has been demonstrated to be efficacious in inducing tumor remission in patients with triple-negative breast cancer (TNBC). However, tumor immune evasion caused by the PD-1/PD-L1 pathway inhibits the immunotherapeutic effect of PD-1/PD-L1 inhibitors against TNBC. Therefore, identifying potential targets for blocking the PD-1/PD-L1 pathway is a compelling strategy for TNBC treatment. Here, we discovered that VGLL4 could inhibit PD-L1 transcription by suppressing STAT3 activation, thereby enhancing the efficacy of anti-PD-1 antibody immunotherapy in TNBC. Low expression of USP15, a deubiquitinating enzyme of VGLL4, was associated with reduced CD8+ T cell infiltration and poor prognosis in TNBC patients. USP15 was found to inhibit PD-L1 transcription, leading to increased CD8+ T cell infiltration and thus enhancing the efficacy of TNBC immunotherapy. Furthermore, SART3 regulated VGLL4 stability and PD-L1 transcription by influencing the nuclear translocation of USP15. In conclusion, our study provides new insights into the biological regulation of PD-L1, identifies a previously unrecognized regulator of this critical immune checkpoint, and highlights potential therapeutic targets for overcoming immune evasion in TNBC.

Gemcitabine Modulates HLA-I Regulation to Improve Tumor Antigen Presentation by Pancreatic Cancer Cells.

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.

Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial.

Pancreatic and colorectal cancers are often KRAS mutated and are incurable when tumor DNA or protein persists or recurs after curative intent therapy. Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). We treated 25 patients (20 pancreatic and five colorectal) who were positive for minimal residual mKRAS disease (ctDNA and/or serum tumor antigen) after locoregional treatment in a phase 1 study of fixed-dose Amph-Peptides-2P and ascending-dose Amph-CpG-7909; study enrollment is complete with patient follow-up ongoing. Primary endpoints included safety and recommended phase 2 dose (RP2D). The secondary endpoint was tumor biomarker response (longitudinal ctDNA or tumor antigen), with exploratory endpoints including immunogenicity and relapse-free survival (RFS). No dose-limiting toxicities were observed, and the RP2D was 10.0 mg of Amph-CpG-7909. Direct ex vivo mKRAS-specific T cell responses were observed in 21 of 25 patients (84%; 59% both CD4+ and CD8+); tumor biomarker responses were observed in 21 of 25 patients (84%); biomarker clearance was observed in six of 25 patients (24%; three pancreatic and three colorectal); and the median RFS was 16.33 months. Efficacy correlated with T cell responses above or below the median fold increase over baseline (12.75-fold): median tumor biomarker reduction was -76.0% versus -10.2% (P < 0.0014), and the median RFS was not reached versus 4.01 months (hazard ratio = 0.14; P = 0.0167). ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors. ClinicalTrials.gov identifier: NCT04853017 .

CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses.

A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment.

Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF.

BACKGROUND: Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers. METHODS: Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database. RESULTS: TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients. CONCLUSIONS: Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.

STEAP1 Knockdown Decreases the Sensitivity of Prostate Cancer Cells to Paclitaxel, Docetaxel and Cabazitaxel.

The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) protein has been indicated as an overexpressed oncoprotein in prostate cancer (PCa), associated with tumor progression and aggressiveness. Taxane-based antineoplastic drugs such as paclitaxel, docetaxel, or cabazitaxel, have been investigated in PCa treatment, namely for the development of combined therapies with the improvement of therapeutic effectiveness. This study aimed to evaluate the expression of STEAP1 in response to taxane-based drugs and assess whether the sensitivity of PCa cells to treatment with paclitaxel, docetaxel, or cabazitaxel may change when the STEAP1 gene is silenced. Thus, wild-type and STEAP1 knockdown LNCaP and C4-2B cells were exposed to paclitaxel, docetaxel or cabazitaxel, and STEAP1 expression, cell viability, and survival pathways were evaluated. The results obtained showed that STEAP1 knockdown or taxane-based drugs treatment significantly reduced the viability and survival of PCa cells. Relatively to the expression of proliferation markers and apoptosis regulators, LNCaP cells showed a reduced proliferation, whereas apoptosis was increased. However, the effect of paclitaxel, docetaxel, or cabazitaxel treatment was reversed when combined with STEAP1 knockdown. Besides, these chemotherapeutic drugs may stimulate the cell growth of PCa cells knocked down for STEAP1. In conclusion, this study demonstrated that STEAP1 expression levels might influence the response of PCa cells to chemotherapeutics drugs, indicating that the use of paclitaxel, docetaxel, or cabazitaxel may lead to harmful effects in PCa cells with decreased expression of STEAP1.

The landscape of objective response rate of anti-PD-1/L1 monotherapy across 31 types of cancer: a system review and novel biomarker investigating.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer treatment. However, only a few patients respond to ICI treatment. Thus, uncovering clinically accessible ICI biomarkers would help identify which patients will respond well to ICI treatment. A comprehensive objective response rate (ORR) data of anti-PD-1/PD-L1 monotherapy in pan-cancer would offer the original data to explore the new biomarkers for ICIs. METHODS: We systematically searched PubMed, Cochrane, and Embase for clinical trials on July 1, 2021, limited to the years 2017-2021, from which we obtained studies centering around anti-PD-1/PD-L1 monotherapy. Finally, 121 out of 3099 publications and 143 ORR data were included. All of the 31 tumor types/subtypes can be found in the TCGA database. The gene expression profiles and mutation data were downloaded from TCGA. A comprehensive genome-wide screening of ORR highly correlated mutations among 31 cancers was conducted by Pearson correlation analysis based on the TCGA database. RESULTS: According to the ORR, we classified 31 types of cancer into high, medium, and low response types. Further analysis uncovered that "high response" cancers had more T cell infiltration, more neoantigens, and less M2 macrophage infiltration. A panel of 28 biomarkers reviewed from recent articles were investigated with ORR. We also found the TMB as a traditional biomarker had a high correlation coefficient with ORR in pan-cancer, however, the correlation between ITH and ORR was low across pan-cancer. Moreover, we primarily identified 1044 ORR highly correlated mutations through a comprehensive screening of TCGA data, among which USH2A, ZFHX4 and PLCO mutations were found to be highly correlated to strengthened tumor immunogenicity and inflamed antitumor immunity, as well as improved outcomes for ICIs treatment among multiple immunotherapy cohorts. CONCLUSION: Our study provides comprehensive data on ORR of anti-PD-1/PD-L1 monotherapy across 31 tumor types/subtypes and an essential reference of ORR to explore new biomarkers. We also screened out a list of 1044 immune response related genes and we showed that USH2A, ZFHX4 and PLCO mutations may act as good biomarkers for predicting patient response to anti-PD-1/PD-L1 ICIs.

The relationship between carbonic anhydrase IX (CAIX) and patient survival in breast cancer: systematic review and meta-analysis.

PURPOSE: Hypoxia is a characteristic of many solid tumours and an adverse prognostic factor for cancer therapy. Hypoxia results in upregulation of carbonic anhydrase IX (CAIX) expression, a pH-regulating enzyme. Many human tissue studies have examined the prognostic value of CAIX expression in breast cancer but have yielded inconsistent results. Therefore, a systematic review and meta-analysis was undertaken to assess the prognostic value of CAIX expression for breast cancer patients. METHODS: The electronic databases were systematically searched to identify relevant papers. The clinical outcomes included disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) in breast cancer patients. Review Manager version 5.4 was employed to analysis data from 23 eligible studies (containing 8390 patients). RESULTS: High CAIX expression was associated with poorer RFS [HR = 1.42, 95% CI (1.32-1.51), p < 0.00001], DFS [HR = 1.64, 95% CI (1.34-2.00), p < 0.00001], and OS [HR = 1.48, 95% CI (1.22-1.80), p < 0.0001]. Heterogeneity was observed across the studies. There was an effect of the CAIX antibody employed, scoring methods, and tumour localisation on CAIX expression. CONCLUSION: CAIX overexpression was significantly associated with poorer RFS, DFS, and OS in breast cancer patients. However, further work in high quantity tissue cohorts is required to define the optimal methodological approach.

Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies.

The tumor-associated antigen mesothelin is expressed at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated. Here, we report the crystal structures of mesothelin that reveal a compact, right-handed solenoid consisting of 24 short helices and connecting loops. These helices form a nine-layered spiral coil that resembles ARM/HEAT family proteins. Glycan attachments have been identified in the structure for all three predicted N-glycosylation sites and confirmed with samples from cell culture and patient ascites. The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been reported previously. The N-terminal half of mesothelin is conformationally rigid, suitable for eliciting specific antibodies, whereas its C-terminal portion is more flexible. The structure of the C-terminal shedding-resistant fragment of mesothelin complexed with a mAb 15B6 displays an extended linear epitope and helps explain the protection afforded by the antibody for the shedding sites. Significance: The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies.

Therapeutic Cancer Vaccines for Nonmelanoma Skin Cancer.

OPINION STATEMENT: The development of immunotherapies for nonmelanoma skin cancer (NMSC) has lagged far behind that for melanoma in the past few decades, given that the majority of cases are surgically curable. Nevertheless, given the steady growth in the incidence rate of NMSC and attendant increase in patients with unresectable or advanced-stage tumors, the demand for systemic therapy is noticeably increasing. To date, the most widely used immunotherapeutic strategies, including immune checkpoint inhibitors and T-cell therapy, have obtained satisfactory results in some patients but not others. Even with an objective response in a fraction of patients, some accompanying adverse events may lead to intolerance and noncompliance. The expanding understanding of immune surveillance and tumor escape has provided us with novel perspectives in the field of immunotherapy. One emerging approach, the therapeutic cancer vaccine, encompasses the potential to newly "prime" T cells by activating antigen presentation in regional lymph nodes and the tumor microenvironment. Immune cells are therefore preconditioned and awakened to be ready to attack tumors. In NMSCs, multiple clinical trials of cancer vaccines are underway. The vaccine targets include tumor-associated antigens, tumor-specific antigens, oncolytic viruses, and toll-like receptors. Although clinical benefits have been shown in specific case reports and trials, various challenges remain to be resolved to guarantee applicability in the general patient population. Standing on the shoulders of pioneers expedites the pace of advances in therapeutic cancer vaccines, making them the rising star in the field of immunotherapy.

Biomaterials-assisted construction of neoantigen vaccines for personalized cancer immunotherapy.

INTRODUCTION: Cancer vaccine represents a promising strategy toward personalized immunotherapy, and its therapeutic potency highly relies on the specificity of tumor antigens. Among these extensively studied tumor antigens, neoantigens, a type of short synthetic peptides derived from random somatic mutations, have been shown to be able to elicit tumor-specific antitumor immune response for tumor suppression. However, challenges remain in the efficient and safe delivery of neoantigens to antigen-presenting cells inside lymph nodes for eliciting potent and sustained antitumor immune responses. The rapid advance of biomaterials including various nanomaterials, injectable hydrogels, and macroscopic scaffolds has been found to hold great promises to facilitate the construction of efficient cancer vaccines attributing to their high loading and controllable release capacities. AREAS COVERED: In this review, we will summarize and discuss the recent advances in the utilization of different types of biomaterials to construct neoantigen-based cancer vaccines, followed by a simple perspective on the future development of such biomaterial-assisted cancer neoantigen vaccination and personalized immunotherapy. EXPERT OPINION: These latest progresses in biomaterial-assisted cancer vaccinations have shown great promises in boosting substantially potentiated tumor-specific antitumor immunity to suppress tumor growth, thus preventing tumor metastasis and recurrence.

Antibody-Drug Conjugates in Prostate Cancer: Where Are we?

Antibody-drug conjugates (ADCs) reflect a new promising approach in prostate cancer, even more so after the practice-changing results in other malignancies, either hematologic or solid. ADCs consist of monoclonal antibodies (mAb) targeted at specific antigens overly expressed on cancer cells compared to normal cells. A cytotoxic payload is attached to the mAb using a stable linker. In prostate cancer, PSMA, STEAP1, TROP2, CD46 and B7-H3 are antigens currently being studied as targets for ADCs. In this paper, we discuss the composition of ADCs and focus on their application and challenges as treatment options in prostate cancer.

Peroxynitrite promotes immune evasion by reducing tumor antigenicity.

A study by Tcyganov et al.1 demonstrates that peroxynitrite, an oxidant abundant in the tumor microenvironment, changes the repertoire of MHC class I peptides presented by tumors and limits immune recognition. Peroxynitrite inhibition in combination with immune checkpoint blockade enhances efficacy preclinically.

A single-beam of light priming the immune responses and boosting cancer photoimmunotherapy.

Mirroring the rapid clinical performance, immune checkpoint blockade (ICB) leads a remarkable clinical advance in combating cancer, but suffers poor response in most cancers. The low presence of tumor-infiltration lymphocytes and the poor immunogenicity in tumor microenvironment (TME) are the main factors hindering the effectiveness of ICB in the treatment of immunological "cold" tumors. Aiming at boosting immune response via TME modulation, we report a near-infrared laser-guided photoimmuno-strategy in which synergistic phototherapy, immune adjuvant, and ICB are integrated into one versatile nanoporphyrin platform. The prepared nanoporphyrins are self-assembled from purpurin18-lipids and have photodynamic/photothermal and immunomodulatory effects that can be tuned under a single laser irradiation, concomitant with fluorescence or MSOT imaging. In this work, the contributions of each component in the nanoporphyrin platform were specified. In particular, phototherapy-driven in situ tumor cell death provided abundant tumor-associated antigens to initiate immune responses. With the assist of spatiotemporally delivered immune adjuvant, phototherapy potentiated tumor immunogenicity, reprogrammed "cold" tumors into "hot" ones, and sensitized tumors to ICB therapy. Further combined with PD-L1 blockade, the photoimmune-strategy substantially stimulated tumor-specific immune-responses and long-term immunological memory against primary tumor, abscopal tumor as well as metastatic foci. Such single light-primed photoimmunotherapy offers a promising solution to overcome common hurdles in ICB treatment and can potentially be integrated into existing clinical practice.

Dual Antigen T Cell Engagers Targeting CA9 as an Effective Immunotherapeutic Modality for Targeting CA9 in Solid Tumors.

Glioblastomas (GBM), the most common malignant primary adult brain tumors, are uniformly lethal and are in need of improved therapeutic modalities. GBM contain extensive regions of hypoxia and are enriched in therapy resistant brain tumor-initiating cells (BTICs). Carbonic anhydrase 9 (CA9) is a hypoxia-induced cell surface enzyme that plays an important role in maintenance of stem cell survival and therapeutic resistance. Here we demonstrate that CA9 is highly expressed in patient-derived BTICs. CA9+ GBM BTICs showed increased self-renewal and proliferative capacity. To target CA9, we developed dual antigen T cell engagers (DATEs) that were exquisitely specific for CA9-positive patient-derived clear cell Renal Cell Carcinoma (ccRCC) and GBM cells. Combined treatment of either ccRCC or GBM cells with the CA9 DATE and T cells resulted in T cell activation, increased release of pro-inflammatory cytokines and enhanced cytotoxicity in a CA9-dependent manner. Treatment of ccRCC and GBM patient-derived xenografts markedly reduced tumor burden and extended survival. These data suggest that the CA9 DATE could provide a novel therapeutic strategy for patients with solid tumors expressing CA9 to overcome treatment resistance. .

Precisely Targeted Nano-Controller of PD-L1 Level for Non-Small Cell Lung Cancer Spinal Metastasis Immunotherapy.

Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin ß3 (ß3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target ß3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM.

AXL/CDCP1/SRC axis confers acquired resistance to osimertinib in lung cancer.

Osimertinib, a third-generation EGFR-TKI, has nowadays been applied to non-small cell lung cancer harboring activated EGFR mutation with or without T790M, but ultimately develop resistance to this drug. Here we report a novel mechanism of acquired resistance to osimertinib and the reversal of which could improve the clinical outcomes. In osimertinib-resistant lung cancer cell lines harboring T790M mutation that we established, expression of multiple EGFR family proteins and MET was markedly reduced, whereas expression of AXL, CDCP1 and SRC was augmented along with activation of AKT. Surprisingly, AXL or CDCP1 expression was induced by osimertinib in a time-dependent manner up to 3 months. Silencing of CDCP1 or AXL restored the sensitivity to osimertinib with reduced activation of SRC and AKT. Furthermore, silencing of both CDCP1 and AXL increased the sensitivity to osimertinib. Either silencing of SRC or dasatinib, a SRC family kinase (SFK) inhibitor, suppressed AKT phosphorylation and cell growth. Increased expression of AXL and CDCP1 was observed in refractory tumor samples from patients with lung cancer treated with osimertinib. Together, this study suggests that AXL/SFK/AKT and CDCP1/SFK/AKT signaling pathways play some roles in acquired osimertinib resistance of non-small cell lung cancer.