Prevent Tumor Progression Research Articles

Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.

Expression of interleukin-8 and integrin β3 predicts prognosis of patients with hepatocellular carcinoma after hepatectomy.

As important components in the tumor microenvironment, interleukin-8 (IL-8) and integrin β3 play a key role in the progression and metastasis of hepatocellular carcinoma (HCC). This study aimed to determine the expression of IL-8 and integrin β3 and their prognostic value in patients with HCC after hepatectomy. We investigated the expression of IL-8 and integrin β3, their clinical significance, as well as their correlation in the cancer tissue of 130 patients with HCC using immunohistochemistry. The prognostic value of IL-8 and integrin β3 was investigated through the follow-up of patients with HCC after hepatectomy. In HCC, IL-8 expression had a positive correlation with integrin β3 expression. Increased expressions of IL-8 and integrin β3 were indicators of tumor progression and poor prognosis in patients with HCC after hepatectomy. IL-8 positive specimens exhibited a higher proportion of macrovascular invasion, larger tumor size, poor differentiation, and advanced tumor-node-metastasis (TNM) stage (P < .05, respectively). Integrin β3 positive group exhibited a higher proportion of TNM III-staged tumors (P < .05). The results indicated that macrovascular invasion, advanced TNM stage, and integrin β3 expression were independent unfavorable prognostic factors in HCC after hepatectomy. Integrin β3 expression was proved to be an independent unfavorable prognostic factor in HCC after hepatectomy. Targeting integrin β3 might be a potential therapeutic approach in preventing tumor progression in HCC.

P3.13D.03 Inhibition of LSD1 Prevented Tumor Progression and Recurrence to Radioimmunotherapy in Small Cell Lung Cancer

P3.13D.03 Inhibition of LSD1 Prevented Tumor Progression and Recurrence to Radioimmunotherapy in Small Cell Lung Cancer

A thermo-responsive chemically crosslinked long-term-release chitosan hydrogel system increases the efficiency of synergy chemo-immunotherapy in treating brain tumors

Glioblastoma multiforme (GBM) is an aggressive and common brain tumor. The blood-brain barrier prevents several treatments from reaching the tumor. This study proposes a Chemo-Immunotherapy synergy treatment chemically crosslinked hydrogel system that is injected into the tumor to treat GBM. The strategy uses doxorubicin and BMS-1 with a thermo-responsive and chemically crosslinked hydrogel for extended drug release into the affected area. The hydrogels are produced by mixing with Chitosan (Chi), modified Pluronic F-127 (PF-127) with aldehyde end group and doxorubicin and then chemically crosslinking the aldehyde and amine bonds to increase the drug retention time. PF-127-CHO/Chi, which gels at body temperatures and chemically crosslinks between PF-127-CHO and Chitosan, increases the time that the drug remains in the affected area and prevents the hydrogel from swelling and compressing surrounding tissue. The drug is released from the chemically crosslinked hydrogels, prevents tumor progression and increases survival for subjects with GBM tumors. The Synergy Chemo-Immunotherapy also allows more efficient treatment of GBM than chemotherapy. The PF-127-CHO/Chi DOX and BMS-1 group have a tumor that is 43 times smaller than the untreated group. These results show that the proposed chemically crosslinking hydrogel is an efficient intratumoral delivery platform for the treatment of tumors.

Vorasidenib- A Paradigm Shift in IDH1- or IDH2-Mutant Low-Grade Glioma Treatment.

Low-grade gliomas (LGGs) pose significant challenges in cancer research and treatment due to their infiltrative nature and tendency for recurrence, making them the most common brain tumour in adults. Most of the LGGs have the propensity to cause notable alterations in the microenvironment of the tumour thus making them difficult to treat. These alterations can be attributed to the prevalent mutations in the genes that produce isocitrate dehydrogenase (IDH) enzymes, especially in grade 2 diffuse gliomas. [1] Despite its inability to provide a complete cure, chemoradiation has been adopted as the standard therapy in grade 3 gliomas since it can lead to long-lasting remission. Chemoradiotherapy, when administered promptly, can help prevent tumour progression, and recurrence after surgery and improve long-term outcomes. Nevertheless, immediate adjuvant chemoradiotherapy is not administered in patients afflicted with tumours containing IDH mutant grade 2 gliomas. This decision is often made to circumvent potential harm such as radiation-induced cognitive problems, chemotherapy-related DNA mutations, and other negative effects on their health. [2] Due to the intricacies associated with the treatment decisions and the inclination to delay aggressive therapies to avoid adverse events, creates a necessity for a novel therapeutic strategy that is both effective and well tolerated. Vorasidenib, an oral medication specifically designed to deal with IDH mutations has displayed promise despite existing challenges. By aiming to specifically target aberrant metabolic pathways triggered by mutant IDH enzymes, Vorasidenib offers a potential treatment capable of interrupting tumour growth and could subsequently result in better patient outcomes. Among the many reasons that make Vorasadenib an appealing option are its capability to penetrate the blood-brain barrier and its promising safety profile, resulting in effective treatment while alleviating potential side effects. [3] Vorasidenib’s efficacy is derived from its ability to halt the metabolic cascades driven by mutant IDH enzymes thus leading to decreased progression of the gliomas. Clinical studies elicit the substantial value Vorasadenib has to offer by enhancing progression-free survival and postponing the advancement of the illness in patients with grade 2 IDH-mutant gliomas. This offers an optimistic prospect for delaying the need for more aggressive treatments in these patients. [2,4] Hence, to conclude Vorasadenib can transform treatment norms and enhance outcomes for those suffering from IDH-mutant LGG. Furthermore, it is crucial to investigate different treatment combinations, finding markers that would help assess clinical response to treatment, which in turn would be an important milestone in the treatment journey.

High Cellular Internalization of Virus-Like Mesoporous Silica Nanoparticles Enhances Adaptive Antigen-Specific Immune Responses against Cancer.

Effective activation of an antigen-specific immune response hinges upon the intracellular delivery of cancer antigens to antigen-presenting cells (APCs), marking the initial stride in cancer vaccine development. Leveraging biomimetic topological morphology, we employed virus-like mesoporous silica nanoparticles (VMSNs) coloaded with antigens and toll-like receptor 9 (TLR9) agonists to craft a potent cancer vaccine. Our VMSNs could be efficiently internalized by APCs to a greater extent than their nonviral structured counterparts, thereby promoting the activation of APCs by upregulating the TLR9 pathway and cross-presenting ovalbumin (OVA) epitopes. In in vivo animal study, VMSN-based nanovaccines triggered substantial CD4+ and CD8+ lymphocyte populations in both lymph nodes and spleen while inducing the effector memory of adaptive T cells. Consequently, VMSN-based nanovaccines suppressed tumor progression and increased the survival rate of B16-OVA-bearing mice in both prophylactic and therapeutic studies. The combination of immune checkpoint blockade (ICB) with the VMSN-based nanovaccine has synergistic effects in significantly preventing tumor progression under therapeutic conditions. These findings highlight the potential of viral structure-mimicking mesoporous silica nanoparticles as promising candidates for antigen-delivering nanocarriers in vaccine development.

Systematic bioinformatics analysis reveals the role of shikonin in blocking colon cancer progression by identifying senescence-induced genes.

Shikonin, a naturally occurring naphthoquinone compound extracted from comfrey plants, has antitumor, anti-inflammatory, and antimicrobial properties. Cell senescence plays a key role in preventing tumor progression. It is unclear whether shikonin has an effect on cell senescence in colon cancer. In the current study, we first determine the IC50 values of shikonin on colon cancer cell lines HT29 and HCT116. Then, we verified the inhibitory effects of shikonin on the proliferation and migration abilities of colon cancer cell lines HT29 and HCT116 using cell counting kit-8, colony formation, and wound healing assays. Next, we identified a series of potential targets using high-throughput mRNA sequencing and identified 210 upregulated and 296 downregulated genes. KEGG profiling revealed eight downregulated genes associated with cell senescence: CCNB3, IL-1α, CXCL8, CDKN2A, MYC, IGFBP3, SQSTM1, and GADD45G. Among them, CXCL8 and CDKN2A were associated with poor prognosis in patients with colon cancer, suggesting that their downregulation by shikonin could improve patient survival. Furthermore, SA-β-galactosidase staining revealed that the percentage of cellular senescence in colon cancer cells was significantly increased after shikonin treatment. Molecular docking revealed that shikonin suppressed colon cancer progression by blocking CXCL8 activity. Based on these findings, we deem that shikonin might induce senescence and exert antitumor activity in colon cancer cells by downregulating CDKN2A and CXCL8. This provides a new molecular mechanism and potential therapeutic target for shikonin to inhibit colon cancer progression.

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin.

Inhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics which prevent tumor progression and metastasis. Here, we utilized an improved and expanded version of positional scanning of substrate combinatorial libraries (PS-SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors of the HGF/MSP activating serine proteases, HGFA, matriptase, and hepsin. These inhibitors have an electrophilic ketone serine trapping warhead and thus form a reversible covalent bond to the protease. We demonstrate that by varying the P2, P3, and P4 positions of the inhibitor with unnatural amino acids based on the protease substrate preferences learned from HyCoSuL, we can predictably modify the potency and selectivity of the inhibitor. We identified the tetrapeptide JH-1144 (8) as a single digit nM inhibitor of HGFA, matriptase and hepsin with excellent selectivity over Factor Xa and thrombin. These unnatural peptides have increased metabolic stability relative to natural peptides of similar structure. The tripeptide inhibitor PK-1-89 (2) has excellent pharmacokinetics in mice with good compound exposure out to 24 h. In addition, we obtained an X-ray structure of the inhibitor MM1132 (15) bound to matriptase revealing an interesting binding conformation useful for future inhibitor design.

Long-term posttransplant survival outcome following bridging locoregional therapy in hepatocellular carcinoma patients: A systematic review and meta-analysis.

Liver transplantation (LT) is essential due to its curative efficacy, but liver-graft shortages have limited its widespread application. Bridging locoregional therapy (LRT) before LT has been performed to prevent tumor progression, and a recent literature review revealed that it is associated with a nonsignificant trend toward better survival outcomes. However, much more information on bridging therapy has become available since then. This meta-analysis aimed to compare the posttransplant survival and HCC recurrence between patients with and without pretransplant bridging LRT. Studies were identified in MEDLINE, SCOPUS, and the Cochrane Library. Two independent researchers screened titles and full articles, extracted relevant data, and conducted a parametric survival analysis. Out of 4794 studies, 18 cohort studies were eligible. The 1-, 3-, and 5-year overall survival (OS) rates were 93.1%, 85.0%, and 79.1% for those in the bridging LRT group, while they were 91.8%, 81.1%, and 75.5% for those who did not receive LRT, respectively. There were no differences in overall survival between these groups (HR 0.90; 0.78-1.05, P = 0.17). Interestingly, we discovered that bridging therapy helped prolong survival significantly in a high-risk population with a long waiting time (HR 0.76; 0.60-0.96, P = 0.02). Unfortunately, bridging LRT did not improve disease-free survival (HR 0.98; 0.86-1.11, P = 0.70). The results indicate that bridging LRT does not generally change post-LT outcomes. However, bridging LRT can significantly improve survival in patients with a long waiting time for LT.

Interleukin-8/CXCR1 Signaling Contributes to the Progression of Pulmonary Adenocarcinoma Resulting in Malignant Pleural Effusion.

Pulmonary adenocarcinoma (PADC) treatment limited efficacy in preventing tumor progression, often resulting in malignant pleural effusion (MPE). MPE is filled with various mediators, especially interleukin-8 (IL-8). However, the role of IL-8 and its signaling mechanism within the fluid microenvironment (FME) implicated in tumor progression warrants further investigation. Primary cultured cells from samples of patients with MPE from PADC, along with a commonly utilized lung cancer cell line, were employed to examine the role of IL-8 and its receptor, CXCR1, through comparative analysis. Our study primarily assessed migration and invasion capabilities, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties. Additionally, IL-8 levels in MPE fluid versus serum, along with immunohistochemical expression of IL-8/CXCR1 signaling in tumor tissue and cell blocks were analyzed. IL-8/CXCR1 overexpression enhanced EMT and CSC properties. Furthermore, the immunocytochemical examination of 17 cell blocks from patients with PADC and MPE corroborated the significant correlation between upregulated IL-8 and CXCR1 expression and the co-expression of IL-8 and CXCR1 in MPE with distant metastasis. In summary, the IL-8/ CXCR1 axis in FME is pivotal to tumor promotion via paracrine and autocrine signaling. Our study provides a therapeutic avenue for improving the prognosis of PADC patients with MPE.

A phase 1 study to evaluate the safety and preliminary efficacy of minnelide given alone or in combination with paclitaxel in advanced gastric cancer.

4033 Background: Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor. Studies using pancreatic cancer cell lines and human xenograft transplants demonstrated that Minnelide prevents tumor progression, increases survival, and causes tumor regression. This study aims to evaluate the safety and antitumor activity of Minnelide and its combination with paclitaxel in patients with advanced gastric cancer (AGC). Methods: This open-label, single-center, dose-escalation phase I study recruited adult patients with previously treated advanced gastric cancer. Patients received Minnelide per oral (PO) daily starting with 1.0 mg for 3weeks and 1week rest schedule, escalating to 1.25mg, and 1.5mg. In combination Regimen, patients received Minnelide starting at a dose of 0.25 mg and escalating by 0.25mg to 1.25mg plus paclitaxel 60-80 mg/m2 intravenously on Day 1, 8, and 15 of each cycle, administered in 4-week cycles. The primary objective was to assess the safety and determine the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy using RECIST v1.1, and survival analysis. Results: Among Regimen A (n = 11), two patients experienced dose-limiting toxicity (DLTs) (Minnelide 1.5 mg: Grade 3 abdominal pain). No DLTs occurred in combination treatment, Regimen B &amp; C (n=25). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4%) and abdominal pain (11.1%). In Regimen C, 71.5% achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. Notably, patients without previous exposure to paclitaxel (n = 4) in the last 2 cohorts of Regimen C, had a confirmed ORR of 50.0%, DCR of 75.0%, the median PFS was 5.3 months (95% CI NE-NE) and the median OS has not reached as some of the patients are still receiving treatment. Conclusions: The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on this Phase I experience a Phase II will be initiated in AGC patients. Clinical trial information: NCT05566834 .

Effect of Rosmarinic Acid on Cell Proliferation, Oxidative Stress, and Apoptosis Pathways in an Animal Model of Induced Glioblastoma Multiforme

In brain tumors, the complexity of the pathophysiological processes such as oxidative stress, cell proliferation, angiogenesis, and apoptosis have seriously challenged the definitive treatment. Rosmarinic acid (RA), as a polyphenolic compound, has been found to prevent tumor progression in some aggressive cancers. This study was designed to evaluate the anticancer effects of RA on brain tumors. Rats were divided into six groups. Implantation of C6 glioma cells was carried out in the caudate nucleus of the right hemisphere. RA at doses of 5, 10, and 20 mg/kg (i.p.) was administered to the treatment groups for seven days. Tumor volume (by MRI imaging), locomotor ability, survival time, histological alterations (by H & E staining), expression of p53 and p21 mRNAs (by RT-PCR), activities of antioxidant enzymes (superoxide dismutase [SOD] and catalase [CAT] by assay kits), expression of caspase-3 and VEGF (by immunohistochemical analysis), and TUNEL-positive cells (by tunnel staining) were analyzed. The results indicated that the RA at a dose of 20 mg/kg reduced the tumor volume, prolonged survival time, increased p53 and p21 mRNAs, attenuated SOD and CAT activities in tumor tissue, elevated caspase-3, and increased the number of TUNEL-positive cells. Furthermore, histological analysis revealed less invasion of tumor cells into the normal parenchyma in rats treated with RA (20 mg/kg). These findings provide evidence that the ability of RA to reduce tumor volume could be related to factors that modulate oxidative stress (SOD and CAT enzymes), cell proliferation (p53 and p21), and apoptosis (caspase-3).

Breast cancer incidence, stage distribution, and treatment shifts during the 2020 COVID-19 pandemic: a nationwide population-level study

BackgroundThe first COVID-19 wave in 2020 necessitated temporary suspension of non-essential medical services including organized cancer screening programs in Belgium. This study assessed the impact of the pandemic on breast cancer (BC) incidence, stage at diagnosis, and management in Belgium in 2020.MethodsAll Belgian residents diagnosed with in situ or invasive BC in 2015–2020 in the nationwide, population-based cancer registry database were included. Incidence trends for 2015–2019 were extrapolated to predict incidence and stage distribution for 2020 and compared with the observed values. National healthcare reimbursement data were used to examine treatment strategies. Exact tumor diameter and nodal involvement, extracted from pathology reports, were analyzed for 2019 and 2020.Results74,975 tumors were selected for analysis of incidence and clinical stage. Invasive BC incidence declined by -5.0% in 2020, with a drop during the first COVID-19 wave (Mar-Jun; -23%) followed by a rebound (Jul-Dec; +7%). Predicted and observed incidence (in situ + invasive) was not different in patients < 50 years. In the 50–69 and 70 + age groups, significant declines of -4.1% and − 8.4% respectively were found. Excess declines were seen in clinical stage 0 and I in Mar-Jun, without excess increases in clinical stage II-IV tumors in Jul-Dec. There was no increase in average tumor diameter or nodal involvement in 2020. Patients diagnosed in Mar-Jun received significantly more neoadjuvant therapy, particularly neoadjuvant hormonal therapy for patients with clinical stage I-II BC.ConclusionsBC incidence decline in 2020 in Belgium was largely restricted to very early-stage BC and patients aged 50 and over. Delayed diagnosis did not result in an overall progression to higher stage at diagnosis in 2020. Observed treatment adaptations in Belgium were successful in prioritizing patients for surgery while preventing tumor progression in those with surgical delay. Continuation of monitoring BC incidence and stage in the future is crucial.

Expression of CD4+ and CD8+ Tumor-Infiltrating Lymphocytes in Oral Squamous Cell Carcinoma and Their Relationship With Clinicopathological Parameters: A Cross-Sectional Study.

Background Oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm of the oral cavity. The tumor microenvironment (TME) is a dynamic ecosystem composed of components contributed by both the tumor and the host. The immune cells of TME, mainly CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs), suppress the proliferation of cancer cells andplay a crucial role in the progression of OSCC. The present study aims to analyze the immunohistochemical expression of CD4+ and CD8+ TILs in OSCC and to compare and correlate them with clinicopathological parameters. Methodology A total of 75 formalin-fixed paraffin-embedded samples of cases diagnosed with primary OSCC wereimmunostained withCD4+ and CD8+ antibodies and their expression was compared with the clinicopathological parameters. Results There was a significant positive correlation between CD4+ and CD8+ expression (r = 0.655, p = 0.001).Both CD4+ (r = -2.37, p = 0.041) and CD8+ (r = -0.348, p = 0.002) expressions negatively correlated with the TNM stage (r = -2.37, p = 0.041) of OSCC. CD8+ expression positively correlated with histopathological grade (r = 0.288, p = 0.012). Conclusions The study findings suggest that CD4+ cells are essential to maintain and sustain CD8+ TIL-mediated anti-tumor response. CD4+ and CD8+ TILs are key players in cell-mediated adaptive immunity and prevent tumor progression and metastasis. Strikingly, the higher grade of tumors despite heavy CD8+ infiltration may possibly be due to cancer immunoediting.

GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder Cancer Cells.

Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an ADAM10-interacting protein to induce selective N-cadherin cleavage. We first demonstrated, in invasive T24 bladder cancer cells, that N-cadherin was cleaved by ADAM10 generating NTF in the extracellular environment and leaving a membrane-anchored CTF1 fragment and that Tspan15 is required for ADAM10 to induce the selective N-cadherin cleavage. Targeting N-cadherin function in cancer is relevant to preventing tumor progression and metastases. For antitumor molecules to inhibit N-cadherin function, they should be complete and not cleaved. We first showed that the GW501516, an agonist of the nuclear receptor PPARβ/δ, decreased Tspan15 and prevented N-cadherin cleavage thus decreasing NTF. Interestingly, the drug did not modify ADAM10 expression, which was important because it could limit side effects since ADAM10 cleaves numerous substrates. By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain.

Abstract 1376: Engineered exosomes for the delivery of PD-L1 siRNA for lung cancer immunotherapy

Abstract Cancer immunosurveillance involves a dynamic interplay between the host’s innate and adaptive immunity. The regulation of programmed death ligand-1 (PD-L1) expression on cancer cells has emerged as an attractive approach for cancer treatment. However, challenges such as the immunosuppressive tumor microenvironment, ineffective trafficking, and tumor antigen heterogeneity limit the applications of cancer immunotherapy for solid tumors. Small interfering RNA (siRNA) against PD-L1 presents a compelling alternative to antibody treatment to reduce PD-L1 presentation on cancer cells, thereby enhancing T-cell detection and preventing tumor progression. Bovine milk/colostrum serve as a biocompatible source for exosomes for delivery biologics such as siRNA. Here, we demonstrate exosomes mediated delivery of siPD-L1 for lung cancer immunotherapy. Exosomes were isolated from bovine colostrum powder using ultracentrifugation. The average particle size of exosomes was 66 ± 2.5 nm, with polydispersity index (pdi) 0.27 ± 0.01 and a zeta potential -9.2 ± 0.70 mV, as analyzed by Zetasizer and validated by atomic force microscopy (AFM) and transmission electron microscopy (TEM). Formulations of exosomes with polyethyleneimine (EPM) and siRNA (1 - 20 μg), when mixed with 5’-32P-labeled siRNA as a tracer resulted in over 90% entrapment of siRNA. Biodistribution studies of exosomes and EPM, with or without the tumor-targeting ligand folic acid (FA), revealed predominantly similar distribution patterns. Notably, FA-EPM exhibited enhanced tumor accumulation compared to EPM, attributed to the overexpression of folate receptors on tumor cells.To assess the functionality of EPM-siRNA, we screened 4 different siPD-L1 sequences in LLC-1 and A549 lung cancer cells. Following 48 h of EPM-siPD-L1 treatment, cells were harvested. Analysis of protein lysates by western blot showed a significant downregulation of the PD-L1 expression, ranging from 55% - 80% in LLC-1 cells and over 80% in A549 cells. In vivo mouse study with orthotopic Lewis lung carcinoma (LL/2-Luc2) tumors is underway to validate the effective silencing of PD-L1 and its effect on tumor inhibition and immune markers. In summary, our targeted EPM technology represents a novel nanoplatform for siRNA therapeutics delivery. As milk/colostrum are the most abundant sources of exosomes, clinical translatability of this novel approach is eminent. Funding: This research work was supported from the Kentucky Lung Cancer Research Program (GB170558) and Immunotherapy CCII CoBRE pilot project (P20GM135004). Keywords: Exosomes, siPD-L1, siRNA delivery, Lung cancer, Immunotherapy Citation Format: Raghuram Kandimalla, Disha N. Moholkar, Margaret Wallen, Chuanlin Ding, Ramesh C. Gupta, Farrukh Aqil. Engineered exosomes for the delivery of PD-L1 siRNA for lung cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1376.

Abstract 3456: The role of particulate matter exposure in racial differences in colorectal cancer mortality in metropolitan Detroit

Abstract Colorectal cancer (CRC) is the third most diagnosed cancer in the United States and the third leading cause of cancer-related deaths. Non-Hispanic Black (NHB) individuals have the highest rates of CRC incidence and mortality in the United States. These disparities are highly influenced by social determinants of health (SDOH). Neighborhood quality, a well-established SDOH, has been shown to influence cancer outcomes, oftentimes more heavily in minorities. Additionally, neighborhood quality is known to influence an individual’s risk of exposure to harmful environmental contaminants including ambient air pollution as a result of systemic racism such as segregation and historic redlining, leading to environmental injustices. Fine particulate matter (PM2.5) exposure has been shown to increase the risk of CRC mortality, however, its effects by race have not yet been examined. We sought to understand whether higher rates of exposure to PM2.5 played a role in racial differences in CRC survival in metropolitan Detroit. Patient data including census tract at diagnosis, demographics, and clinical features were obtained from the metropolitan Detroit cancer surveillance system registry. Ambient PM2.5 concentration data at the census tract were obtained from the Environmental Protection Agency (EPA) Remote Sensing Information Gateway (RSIG) and converted to annual averages to use in an interval-censored Cox proportional hazards regression model. We found that PM2.5 exposure partly attenuated the effect of race on overall mortality in all patients (NHB vs NHW: Hazard Ratio (HR) = 1.24, 95% Confidence Interval (CI) 1.20 - 1.27, p &amp;lt; 0.0001, NHB vs NHW after accounting for PM2.5: HR = 1.19, 95% CI = 1.16 - 1.23 p &amp;lt; 0.0001) and the effect was stronger among patients under 50 than over 50, though still significant in both models. Additionally, the effect of PM2.5 on mortality was much stronger among NHB patients than NHW patients (NHB HR = 1.30, 95% CI = 1.17 - 1.45, p &amp;lt; 0.0001; NHW HR = 1.06, 95% CI = 1.02 - 1.11 p = 0.008) and especially strong among NHB patients under 50 (HR = 2.51, 95% CI = 2.38 - 3.38, p &amp;lt; 0.0001) compared to any other group. We conclude that ambient air pollution, particularly PM2.5, disproportionately affects mortality risk in NHB CRC patients. These results highlight the importance of environmental justice research in biomedical research, and the need for a better understanding of environmental impact on tumor biology to prevent tumor progression and mortality among all patients. Citation Format: Natalie Gail Snider, Theresa Hastert, Gregory Dyson, Carina Gronlund, Elena M. Stoffel, Ed Peters, Laura Rozek, Ann Schwartz, Kristen Purrington. The role of particulate matter exposure in racial differences in colorectal cancer mortality in metropolitan Detroit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3456.

PAD4 controls tumor immunity via restraining the MHC class II machinery in macrophages

Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood whether and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we reveal that peptidylarginine deiminase 4 (PAD4) exhibits the highest expression among common PTM enzymes in TAMs and negatively correlates with the clinical response to immune checkpoint blockade. Genetic and pharmacological inhibition of PAD4 in macrophages prevents tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage major histocompatibility complex (MHC) class II expression and Tcell effector function. Mechanistically, PAD4 citrullinates STAT1 at arginine 121, thereby promoting the interaction between STAT1 and protein inhibitor of activated STAT1 (PIAS1), and the loss of PAD4 abolishes this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC class II machinery in macrophages and enhancing Tcell activation. Thus, the PAD4-STAT1-PIAS1 axis is an immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.

New insights into the role of mast cells as a therapeutic target in cancer through the blockade of immune checkpoint inhibitors.

Mast cells release different anti-and pro-inflammatory agents changing their role from protective to pro-inflammatory cells involved in the progression of different pathological conditions, including autoimmune diseases and tumors. Different mediators released by mast cells are involved in their biological activities which may be anti-tumorigenic and/or pro-tumorigenic. For these reasons, tumor mast cells have been considered a novel therapeutic target to prevent tumor progression and metastatic process. Many different agents have been suggested and used in the past pre-clinical and clinical settings. Among the novel immunotherapeutic approaches to cancer treatment, different immune checkpoint inhibitors targeting PD-1/PDL-1 have been used in the treatment of many human tumors improving overall survival. In this context, inhibition of mast cell activity may be considered a novel strategy to improve the efficacy of anti-PD-1/PDL-1 therapy. The blockade of the PD-1/PD-L1 interaction may be suggested as a useful and novel therapeutic approach in the treatment of tumors in which mast cells are involved.

Precise Photodynamic Therapy by Midkine Nanobody-Engineered Nanoparticles Remodels the Microenvironment of Pancreatic Ductal Adenocarcinoma and Potentiates the Immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.