Metastasis Of Solid Tumors Research Articles

Thymoma Profile at Dr. Moewardi General Hospital: Does Thymoma Size Really Affect Distant Metastasis?

Introduction: Size is a predictor factor of a patient’s prognosis and metastasis in solid tumors. This study determined the relationship between thymoma size and distant metastasis. Methods: A cohort retrospective study using medical record data was conducted at Dr. Moewardi General Hospital, Surakarta, from January 2019 to August 2021. Of 1,430 thoracic oncology patients, 150 (10%) had mediastinal mass with thymoma as the majority (48.6%). About 73 thymoma patients were included. The size of the thymoma was the dependent variable, and the metastasis (distant and non-distant) was the independent variable. The cut-off point of thymoma size was determined with receiver operating characteristic (ROC) analysis. The correlation of thymoma size with distant metastasis was analyzed with the Chi-Square test, and p < 0.05 was considered significant. Results: Thymoma was predominated by males (53.4%), the mean age was 43 ± 16 years old, and dyspnea was the most common symptom. Metastatic lesions were found in 87.7% of the patients, and the most common metastatic sites were intrathoracic (79.5%), followed by axillary lymph nodes (49.3%), bone (21.9%), liver (20.5%), and brain (1.4%). The cut-off value of thymoma size was 8.25 cm, indicating that >8.25 cm was categorized as large thymoma. Distant metastasis was found in 86.0% of large thymoma patients. The large tumors tend to spread into various sites (OR = 5.39; 95% CI 2.8-32.6; p = 0.002). Conclusion: Thymoma must be taken into account when there are male patients in their forties presented with dyspnea and mediastinal mass. The cut-off point of 8.25 cm for the thymoma size can predict distant metastasis.

THE SYSTEMATIC REVIEW OF ADIPOCYTES IN ACUTE LEUKEMIA

Background: Adipose tissue, a major cell type in the bone marrow microenvironment, plays a crucial role in the development and progression of cancer. Adipocytes, which make up the majority of cells in adipose tissue, exhibit distinct metabolic roles, replication and development abilities, cytokine production, and reactions to external stimuli. Adipocytes are abundant in bone marrow, a key site of metastasis for solid tumors and a crucial microenvironment for hematological malignancies. The aim: This study aims to determine the association of adipocytes in acute leukemia. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like PubMed and ScienceDirect, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Results: In the PubMed database, the results of our search brought up 27 articles, whereas the results of our search on ScienceDirect brought up 281 articles. The results of the search conducted by title screening yielded a total 14 articles for PubMed and 3 articles for ScienceDirect. We compiled a total of 12 papers, 10 of which came from PubMed and 2 of which came from ScienceDirect. We excluded 4 review articles, 2 articles having ineligible subjects, and 1 article having insufficient outcomes. In the end, we included five research that met the criteria. Conclusion: Acute leukemia cells have various effects on adipocytes which alter adipogenic differentiation capacities or adipocyte lipolysis and promote bone marrow adipocyte remodeling. Adipocytes play a crucial role in acute leukemia cell survival and their treatment.

Addition of metastasis-directed therapy to standard-of-care systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): Results of a multicenter, randomized phase II trial.

603 Background: Standard treatment of oligometastatic pancreatic ductal adenocarcinoma (PDAC) consists of multi-agent chemotherapy, although outcomes remain poor. We tested the hypothesis that the addition of comprehensive metastasis-directed therapy (MDT) to standard-of-care systemic therapy would improve progression-free survival (PFS) compared with systemic therapy alone. Methods: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a multicenter phase II basket trial randomizing patients with ≤ 5 solid tumor metastases 1:1 to MDT plus systemic therapy versus systemic therapy alone. Each histology-specific basket was pre-specified and independently powered for the primary endpoint of PFS; here we present results of the pancreatic cancer basket. Progression was defined by radiographic criteria (RECIST v1.1), clinical events, or death. Patients were stratified at randomization by number of metastases (1-2 vs 3-5), number of prior lines of systemic therapy (0-1 vs 2+), and cancer antigen 19-9 (CA-19-9) level (<90U/ml vs ≥90U/ml). Exploratory endpoints included systemic immune response measures. The cutoff date for the primary analysis was September 1, 2023. ClinicalTrials.gov registration: NCT03599765. Results: Between March 2019 and February 2023, 41 patients with oligometastatic PDAC were randomized and 40 were eligible for PFS analysis (MDT arm: 19 patients; control arm: 21 patients). Baseline characteristics were well-balanced between arms. Thirty-one patients experienced progression or death; median follow-up time for censored patients was 9.9 months. The MDT arm had significantly longer PFS compared to the systemic therapy arm (median PFS 10.3 versus 2.5 months; log-rank p=0.006). After stratification, the estimated PFS hazard ratio was 0.43 (95% confidence interval: 0.20, 0.94; p=0.03) for MDT compared with systemic therapy. There were no grade 3 or greater adverse events with at least possible attribution to MDT, and only one grade 2 adverse event possibly related to treatment in the MDT arm occurred. Increased systemic T-cell stimulatory cytokines, CD8+ T-cell activation, CD8+ T-cell proliferation, and T-cell receptor clonal expansion following treatment were associated with the MDT arm compared with the control arm (all p<0.05). Conclusions: Among patients with oligometastatic PDAC, the combination of MDT plus systemic therapy was associated with improved PFS compared with systemic therapy alone. Further exploration in phase III trials is warranted, as is investigation into the potential therapeutic implications of systemic immune activation associated with MDT receipt. Clinical trial information: NCT03599765 .

ZC3H12A inhibits tumor growth and metastasis of breast cancer under hypoxic condition via the inactivation of IL-17 signaling pathway

ABSTRACT Hypoxia is a major contributor to tumor microenvironment (TME) and metastasis in most solid tumors. We seek to screen hypoxia-related genes affecting metastasis in breast cancer and to reveal relative potential regulatory pathway. Based on gene expression profiling of GSE17188 dataset, differential expressed genes (DEGs) were identified between highly metastatic breast cancer cells under hypoxia and samples under normoxia. The protein–protein interaction (PPI) network was utilized to determine hub genes. The gene expression profiling interactive analysis database (GEPIA2) and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were employed to quantify hub genes. Moreover, overexpression of zinc finger CCCH-type containing 12A (ZC3H12A) was performed both in breast cancer cells and xenograft mouse model to determine the role of ZC3H12A. We identified 134 DEGs between hypoxic and normoxic samples. Based on PPI analysis, 5 hub genes interleukin (IL)-6, GALN (GAL), CD22 molecule (CD22), ZC3H12A and TNF receptor associated factor 1 (TRAF1) were determined; the expression levels of TRAF1, IL-6, ZC3H12A and GAL were remarkably downregulated while CD22 was upregulated in breast cancer cells. Besides, patients with higher expression of ZC3H12A had favorable prognosis. Overexpression of ZC3H12A could inhibit metastasis and tumor growth of breast cancer; overexpression of ZC3H12A downregulated the expression of IL-17 signaling pathway-related proteins such as IL-17 receptor A (IL-17RA), IL-17A and nuclear factor κB activator 1 (Act1). This study reveals ZC3H12A and IL-17 signaling pathway as potential therapeutic targets for hypoxic breast cancer.

Role of Platelet Activation in the Development and Metastasis of Solid Tumors

Role of Platelet Activation in the Development and Metastasis of Solid Tumors

Oncolytic virus enhanced CAR T cell therapy in killing solid tumors

The application of chimeric antigen receptor (CAR)-expressing T cells has received considerable attention lately, particularly in hematological malignancies. However, whether these altered T cells are therapeutically efficient in treating solid tumors remains unclear. There are some main challenges faced by CAR-T in the setting of solid cancers: identification, trafficking, and immunosuppressive tumor microenvironment (TME). The effectiveness of CAR T cells relies heavily on their ability to migrate and infiltrate these tumors. Oncolytic viruses (OVs) are unique in their ability to selectively invade and eradicate cancerous tissue. Additionally, OVs stimulate the body’s innate immune response and activate tumor-targeted adaptive immune responses, further enhancing their effectiveness in combating cancer. As a result, they exert an influence on T cell movement inside the TME and the performance of effector cells. This review examines the ramifications of incorporating OVs and CAR T cells for solid tumor therapy, while also considering the most recent findings. Furthermore, the integration of OVs with CAR T cells has shown the ability to increase the cytotoxicity of CAR T cells towards solid tumor cells. Thus, combining OVs and CAR T cell treatment may prove to be a potent tactic in combating T cell metastasis and invasion in solid tumours. Additionally, this approach exhibits vast potential for application.

Hypoxia-Responsive Tetrameric Supramolecular Polypeptide Nanoprodrugs for Combination Therapy.

Despite the intense progress of photodynamic and chemotherapy, however, they cannot prevent solid tumor invasion, metastasis, and relapse, along with inferior efficacy and severe side effects. The hypoxia-responsive nanoprodrugs integrating photodynamic functions are highly sought to address the above-mentioned problems and overcome the tumor hypoxia-reduced efficacy. Herein, a hypoxia-responsive tetrameric supramolecular polypeptide nanoprodrug (SPN-TAPP-PCB4) is constructed from the self-assembly of tetrameric porphyrin-central poly(l-lysine-azobenzene-chlorambucil) (TAPP-(PLL-Azo-CB)4) and an anionic water-soluble [2]biphenyl-extended-pillar[6]arene (AWBpP6) via the synergy of hydrophobic, π-π stacking, and host-guest interactions. Upon laser irradiation, the central TAPP can convert oxygen to generate single oxygen (1 O2 ) to kill tumor cells. Furthermore, under the acidic and PDT-aggravated hypoxia tumor cell microenvironment, SPN-TAPP-PCB4 is rapidly disassembled, and then efficiently releases activated CB through the hypoxic-responsive cleavage of azobenzene linkages. Both in vitro and in vivo biological studies showcase synergistic cancer-killing actions between photodynamic therapy (PDT) and chemotherapy (CT) with negligible toxicity. Consequently, this supramolecular polypeptide nanoprodrug offers an effective strategy to design a hypoxia-responsive nanoprodrug for a potential combo PDT-CT transition.

Comparative analysis of the use of B16 melanoma and epidermoid Lewis lung carcinoma models for preclinical studies of compounds with a putative antitumor effect

Introduction The search for new compounds with putative antitumor effects and the development of domestic anticancer and antimetastatic drugs based on them is a priority task for specialists in the field of medical chemistry, experimental pathophysiology and pharmacology. Melanoma B16 and Lewis lung epidermoid carcinoma are universal models for evaluating the effect of compounds with putative antitumor action on the primary focus of tumor growth and the process of tumor cells dissemination.The aim of the work is to determine the feasibility of using models of solid tumor growth and metastasis activity of Lewis lung epidermoid carcinoma and B16 melanoma for preclinical studies of antitumor and antimetastatic pharmacological activity of hybrid organotin compounds depending on experimental objectives.Materials and methods The experimental part was performed on C57B1/6 mice (females). Hybrid organotin compounds were administered five times, intraperitoneal, the beginning of treatment – 48 hours after tumor cells transplantation in the same regimes for both models. In this work, the most effective (375 mg/kg and 250 mg/kg, respectively) and toxic (500 mg/kg and 375 mg/kg, respectively) doses of the leader hybrid organotin compounds Me3 (bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethytin) and Me5 ((3,5-di-tert-butyl-4-hydroxyphenylthiolate)triphenyltin) were used.Results At all stages of the experiment on both models of tumor growth we obtained similar results characterizing the pharmacological activity of the tested compounds: moderate antitumor and high antimetastatic effect. The rates of growth and tumor process development are comparable and convenient for planning preclinical studies in vivo and can be interchangeable.Discussion The Lewis lung model of epidermoid carcinoma has a higher degree of convenience for data interpretation (number of metastatic foci in the lungs) when conducting exploratory analysis of pharmacological activity in a wide range of doses. When studying pathogenetic peculiarities of metastasis under the action of compounds with presumed antitumor action due to the possibilities of contrast immunohistochemical staining of tumor cells, the B16 melanoma model has an advantage. In our experiment with immunohistochemical staining for Melan A the hematogenic pathway of metastasis through the bloodstream is clearly traced.Conclusion For exploratory screening studies to select promising candidates for in-depth study it is reasonable to use the Lewis lung epidermoid carcinoma model. The B16 melanoma model is more informative for in-depth study of compounds that have proven to be effective.

Delineating spatial cell-cell interactions in the solid tumour microenvironment through the lens of highly multiplexed imaging.

The growth and metastasis of solid tumours is known to be facilitated by the tumour microenvironment (TME), which is composed of a highly diverse collection of cell types that interact and communicate with one another extensively. Many of these interactions involve the immune cell population within the TME, referred to as the tumour immune microenvironment (TIME). These non-cell autonomous interactions exert substantial influence over cell behaviour and contribute to the reprogramming of immune and stromal cells into numerous pro-tumourigenic phenotypes. The study of some of these interactions, such as the PD-1/PD-L1 axis that induces CD8+ T cell exhaustion, has led to the development of breakthrough therapeutic advances. Yet many common analyses of the TME either do not retain the spatial data necessary to assess cell-cell interactions, or interrogate few (<10) markers, limiting the capacity for cell phenotyping. Recently developed digital pathology technologies, together with sophisticated bioimage analysis programs, now enable the high-resolution, highly-multiplexed analysis of diverse immune and stromal cell markers within the TME of clinical specimens. In this article, we review the tumour-promoting non-cell autonomous interactions in the TME and their impact on tumour behaviour. We additionally survey commonly used image analysis programs and highly-multiplexed spatial imaging technologies, and we discuss their relative advantages and limitations. The spatial organization of the TME varies enormously between patients, and so leveraging these technologies in future studies to further characterize how non-cell autonomous interactions impact tumour behaviour may inform the personalization of cancer treatment.​.

Bone marrow vasculature advanced in vitro models for cancer and cardiovascular research.

Cardiometabolic diseases and cancer are among the most common diseases worldwide and are a serious concern to the healthcare system. These conditions, apparently distant, share common molecular and cellular determinants, that can represent targets for preventive and therapeutic approaches. The bone marrow plays an important role in this context as it is the main source of cells involved in cardiovascular regeneration, and one of the main sites of liquid and solid tumor metastasis, both characterized by the cellular trafficking across the bone marrow vasculature. The bone marrow vasculature has been widely studied in animal models, however, it is clear the need for human-specific in vitro models, that resemble the bone vasculature lined by endothelial cells to study the molecular mechanisms governing cell trafficking. In this review, we summarized the current knowledge on in vitro models of bone marrow vasculature developed for cardiovascular and cancer research.

Exosomes secreted by metastatic cancer cells promotes epithelial mesenchymal transition in small cell lung carcinoma: The key role of Src/TGF-β1 axis

Exosome-mediated epithelial mesenchymal transition (EMT) is key to cancer metastasis. c-Src is involved in the secretion of exosomes and initiation of EMT. Effects of exosomes from metastatic non-small cell lung carcinoma (NSCLC) cells on the EMT process in primary NSCLC cells were assessed. Levels of c-Src in NSCLC tissues were detected and the influence of exosomes from metastatic NSCLC cells on the exosome secretion and EMT process in primary NSCLC cells was assessed. The expression of c-Src was modulated, and the influence on the secretion of exosomes and EMT initiation was evaluated. The level of c-Src was higher in NSCLC specimen and NSCLC cells with promoted EMT process. The suppression of c-Src inhibited secretion of exosomes. Exosomes from metastatic NSCLC cells enhanced migration and invasion abilities of primary NSCLC cells, which had identical effects to c-Src overexpression. The suppression of c-Src inhibited growth and metastasis of solid tumors as well as secretion of exosomes, while the injection of exosomes with c-Src overexpression promoted lung metastasis. TGF-β1 restored the invasion and migration abilities even with c-Src knockdown. The exosomes from metastatic NSCLC cells with high c-Src expression of can increase c-Src level in primary NSCLC cells, contributing to the promoted EMT process through TGF-β1 pathway.

Selective targeting of α7 nicotinic acetylcholine receptor by synthetic peptide mimicking loop I of human SLURP-1 provides efficient and prolonged therapy of epidermoid carcinoma in vivo.

α7-Type nicotinic acetylcholine receptor (α7-nAChR) promotes the growth and metastasis of solid tumors. Secreted Ly6/uPAR-Related Protein 1 (SLURP-1) is a specific negative modulator of α7-nAChR produced by epithelial cells. Here, we investigated mechanisms of antiproliferative activity of recombinant SLURP-1 in epidermoid carcinoma A431 cells and activity of SLURP-1 and synthetic 21 a.a. peptide mimicking its loop I (Oncotag) in a xenograft mice model of epidermoid carcinoma. SLURP-1 inhibited the mitogenic pathways and transcription factors in A431 cells, and its antiproliferative activity depended on α7-nAChR. Intravenous treatment of mice with SLURP-1 or Oncotag for 10days suppressed the tumor growth and metastasis and induced sustained changes in gene and microRNA expression in the tumors. Both SLURP-1 and Oncotag demonstrated no acute toxicity. Surprisingly, Oncotag led to a longer suppression of pro-oncogenic signaling and downregulated expression of pro-oncogenic miR-221 and upregulated expression of KLF4 protein responsible for control of cell differentiation. Affinity purification revealed SLURP-1 interactions with both α7-nAChR and EGFR and selective Oncotag interaction with α7-nAChR. Thus, the selective inhibition of α7-nAChRs by drugs based on Oncotag may be a promising strategy for cancer therapy.

Novel human lymph node-derived matrix supports the adhesion of metastatic oral carcinoma cells

Background3D culture is increasingly used in cancer research, as it allows the growth of cells in an environment that mimics in vivo conditions. Metastases are the primary cause of morbidity and mortality in cancer patients, and solid tumour metastases are mostly located in lymph nodes. Currently, there are no techniques that model the pre-metastatic lymph node microenvironment in vitro. In this study, we prepared a novel extracellular matrix, Lymphogel, which is derived from lymph nodes, mimicking the tumour microenvironment (TME) of metastatic carcinoma cells. We tested the suitability of the new matrix in various functional experiments and compared the results with those obtained using existing matrices.MethodsWe used both commercial and patient-derived primary and metastatic oral tongue squamous cell carcinoma (OTSCC) cell lines. We characterized the functional differences of these cells using three different matrices (human uterine leiomyoma-derived Myogel, human pre-metastatic neck lymph node-derived Lymphogel (h-LG), porcine normal neck lymph node-derived Lymphogel (p-LG) in proliferation, adhesion, migration and invasion assays. We also performed proteomic analyses to compare the different matrices in relation to their functional properties.ResultsOTSCC cells exhibited different adhesion and invasion patterns depending on the matrix. Metastatic cell lines showed improved ability to adhere to h-LG, but the effects of the matrices on cell invasion fluctuated non-significantly between the cell lines. Proteomic analyses showed that the protein composition between matrices was highly variable; Myogel contained 618, p-LG 1823 and h-LG 1520 different proteins. The comparison of all three matrices revealed only 120 common proteins. Analysis of cellular pathways and processes associated with proteomes of each matrix revealed similarities of Myogel with h-LG but less with p-LG. Similarly, p-LG contained the least adhesion-related proteins compared with Myogel and h-LG. The highest number of unique adhesion-related proteins was present in h-LG.ConclusionsWe demonstrated that human pre-metastatic neck lymph node-derived matrix is suitable for studying metastatic OTSCC cells. As a whole-protein extract, h-LG provides new opportunities for in vitro carcinoma cell culture experiments.

A photothermal driven chemotherapy for the treatment of metastatic melanoma

Solid tumors are abnormal mass of tissue, which affects the organs based on its malignancy and leads to the dysfunction of the affected organs. The major problem associated with treatment of solid tumors is delivering anticancer therapeutics to the deepest layers/core of the solid tumor. Deposition of excessive extracellular matrix (ECM) hinders the therapeutics to travel towards the core of the tumor. Therefore, conventional anticancer therapeutics can only reduce the tumor size and that also for a limited duration, and tumor recurrence occurs once the therapy is discontinued. Additionally, by the time the cancer is diagnosed, the cancer cells already started affecting the major organs of the body such as lung, liver, spleen, kidney, and brain, due to their ability to metastasize and lung is the primary site for them to be infiltrated. To facilitate the anticancer therapeutics to penetrate the deeper layers of tumor, and to provide concurrent treatment of both the solid tumor and metastasis, we have designed and developed a Bimodal Light Assisted Skin Tumor and Metastasis Treatment (BLAST), which is a combination of photothermal and chemotherapeutic moieties. The BLAST is composed of 2D boron nitride (BN) nanosheet with adsorbed molecules of BCL-2 inhibitor, Navitoclax (NAVI) on its surface, that can breakdown excessive ECM network and thereby facilitate dissociation of the solid tumor. The developed BLAST was evaluated for its ability to penetrate solid tumors using 3D spheroids for the uptake, cytotoxicity, growth inhibition, reactive oxygen species (ROS) detection, penetration, and downregulation of proteins upon laser irradiation. The in vivo therapeutic studies on a skin cancer mice model revealed that the BLAST with and without laser were able to penetrate the solid tumor, reduce tumor volume in mice, dissociate the protein network, and prevent lung metastasis as confirmed by immunohistochemistry and western blot analysis. Post analysis of serum and blood components revealed the safety and efficacy of BLAST in mice. Hence, the developed BLAST holds strong promise in solid tumor treatment and metastasis prevention simultaneously.

Crowding phenomenon in breast cancer as a prognostic factor

Purpose: to evaluate the crowding-induced morphological changes in invasive breast carcinoma and compare the data obtained with the parameters of the tumor progression. Material and Methods. The study group included 107 patients (mean age: 57.2 ± 11.2 years) who did not receive neoadjuvant chemotherapy. Breast cancer morphological and immunohistochemical images were studied. The histological type of breast cancer was determined according to WHO recommendations (The WHO Classification of Breast Tumors, 5th Edition, 2019). The study included only cases with invasive breast carcinoma of no specific type. Clinical parameters were assessed using the patients' medical history. Statistical analysis was carried out using the Statistica 10.0 program. A p-value of 0.05 or lower was considered statistically significant. Results. The phenomenon of crowding in breast cancer was shown to be associated with lymph node metastases, with intratumoral heterogeneity of particular importance. The phenomenon of crowding was morphologically confirmed in all cases (n=40) with lymph node metastases in solid tumors. In these solid tumor structures, a decrease in the expression level of the proliferative index Ki67 was observed. In tumor sites with the evidence of crowding phenomenon in solid structures with lymph node metastasis, positive expression of integrin β1 was less frequently observed. Conclusion. Te results obtained suggest that the mechanism that initiates the process of tumor cell invasion may be based on crowding and basal cell extrusion, while the patterns found are a manifestation of changes in cell properties with the acquisition of a higher potential for mobility and cell migration.

Primary assessment of medicines for expected migrastatic potential with holographic incoherent quantitative phase imaging.

Solid tumor metastases cause most cancer-related deaths. The prevention of their occurrence misses suitable anti-metastases medicines newly labeled as migrastatics. The first indication of migrastatics potential is based on an inhibition of in vitro enhanced migration of tumor cell lines. Therefore, we decided to develop a rapid test for qualifying the expected migrastatic potential of some drugs for repurposing. The chosen Q-PHASE holographic microscope provides reliable multifield time-lapse recording and simultaneous analysis of the cell morphology, migration, and growth. The results of the pilot assessment of the migrastatic potential exerted by the chosen medicines on selected cell lines are presented.

Therapeutic CAR T cells differentiate into diverse memory and exhausted T cell subsets in vivo to provide long-term protection from relapse and metastasis of solid tumors.

Abstract Canonical memory T cell differentiation is programmed during the early stages of priming by a multitude of variables such as TCR signal strength, duration of antigenic exposure, and the milieu of cytokines. A combination of such stochastic variables in vivo, drive a heterogeneity in T cell priming that leads to the generation of distinct subsets of T cell effector and memory lineages. Contrarily, CAR T cell priming is largely homogenous and the diversity of the ensuing memory CAR T cells following adoptive immunotherapy remains largely unknown. In this study, we show that following adoptive immunotherapy into solid tumor bearing mice, syngeneic CAR T cells differentiate into distinct memory T cell subsets. In the peripheral tissues and lymphoid organs, CAR T cells subsets of central memory (T CM), effector memory (T EM) and resident memory (T RM) were fully represented. Furthermore, within the tumor microenvironment, distinct lineages of exhausted T cells such as progenitor exhausted (T PEX) and terminally exhausted (T EX) CAR T cells were found. When benchmarked against gold-standard T cells programmed in vivo by viral infections, the subsets of CAR memory and exhausted T cells demonstrated the hallmark qualities of protection from metastasis, and responsiveness to checkpoint blockade, respectively. These findings are among the first to demonstrate that CAR T cells differentiate into a full-spectrum of memory and exhausted T cell subsets in therapeutic applications against solid tumors. Comprehensive understandings of CAR T cell memory and exhaustion programs would be critical in developing therapeutic CAR T cells that provide long-term protection from tumor relapse, tumor metastasis and responsiveness to checkpoint blockade. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number F32CA265056. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Insight into Tumor Hypoxia: Radionuclide-based Biomarker as Diagnostic Tools.

The radiolabeled tracers have been extensively utilized to access various physiological and pathological conditions non-invasively, such as cancers, inflammation, and organ-specific imaging. These tracers demonstrate and study tumor hypoxia in several malignancies. Hypoxia is commonly seen in solid tumors.Tumor Hypoxia is a non-physiological condition of reduced oxygen concentration in the tumor. Hypoxia is associated with adverse outcomes such as treatment resistance and metastases in solid tumors. Tumor hypoxia may result in resistance to radiation therapy and chemotherapy, leading to a poor prognosis.It is one of the clinically paramount factors in treatment planning. Various chemical scaffolds are labeled with compatible radioisotopes for imaging hypoxia by Single-photon emission computed tomography (SPECT) and Positron emission tomography (PET). Radionuclides, such as [18F]Flourine, [99mTc]Technetium, [131I]Iodine, [124I]Iodine, and [64Cu]Copper are used for incorporation into different chemical scaffolds.Among them, [18F]Flourine and [64Cu] Copper tagged radiopharmaceuticals are most explored, such as [18F]FMISO, [18F]FAZA, [18F]FETNIM, and N4-methyl thiosemicarbazone [64Cu][Cu (ATSM)]. Some of the promising scaffolds for imaging hypoxia are [18F]EF1, [18F]EF5, [18F]EF3, and [18F]HX4. This review is focused on developing radiochemistry routes to synthesize different radiopharmaceuticals for imaging hypoxia in clinical and preclinical studies, as described in the literature. The chemist and radiochemist exerted enormous efforts to overcome these obstacles. They have successfully formulated multiple radiopharmaceuticals for hypoxia imaging. Radionuclide incorporation in high selectivity and efficiency (radiochemical yield, specific activity, purity, and radio-scalability) is a need for application perspective. Versatile chemistry, including nucleophilic and electrophilic substitutions, allows the direct or indirect introduction of radioisotopes into molecules of interest. This review will discuss the chemical routes for synthesizing and utilizing different precursors for radiolabeling withradionuclides.We will briefly summaries these radio-labeled tracers' application and biological significance.

Immunotherapeutic Hydrogel with Photothermal Induced Immunogenic Cell Death and STING Activation for Post‐Surgical Treatment

AbstractPost‐surgical tumor recurrence remains a major clinical concern for patients with malignant solid tumors. Herein, an immunotherapeutic hydrogel (SAPBA/ZMC/ICG) is developed by incorporating metal ion‐cyclic dinucleotide (CDN) nanoparticles (Zn‐Mn‐CDN, ZMC) and a photosensitizer (indocyanine green, ICG) into phenylboronic acid (PBA)‐conjugated sodium alginate (SAPBA) for photothermal therapy (PTT)‐triggered in situ vaccination to inhibit post‐surgical recurrence and metastasis of malignant tumors. The gelation of SAPBA/ZMC/ICG in the residual tumors can achieve accurate local PTT and the local sustained release of CDN and Mn2+ with minimal detrimental off‐target toxic effects. Furthermore, CDN, which is an agonist of the stimulator of interferon genes (STING), along with Mn2+ can activate the STING pathway and trigger type‐I‐IFN‐driven immune responses against tumors. Therefore, the immunotherapeutic hydrogel with enhanced immune response by STING agonist and PTT‐induced immunogenic cell death (ICD) reprograms the post‐surgical immunosuppressive microenvironment, substantially decreasing the post‐surgical recurrence and metastasis of solid tumors in multiple murine tumor models when administered during surgical resection. Taken together, PTT‐triggered and STING‐mediated in situ cancer vaccination is an effective therapeutic intervention for post‐surgical recurrence and metastasis of tumors.

Abstract 3466: Microbial neoantigen vectors for cancer immunotherapy

Abstract Cancers employ a variety of immunosuppressive and evasive mechanisms to avoid detection by the immune system and prevent tumor neoantigen-mediated elimination. In recent years, tumor-specific neoantigen vaccines have shown significant promise—promoting tumor regression and increasing survival benefit in certain malignancies by therapeutically directing the immune system to target previously protected tumor specific antigens. However, despite encouraging preclinical data, objective and durable responses have remained elusive—highlighting a requirement for improved therapeutic platforms that permit delivery and targeting of diverse sets of tumor antigens to enhance the efficacy of cancer vaccines. Through synthetic biology, we have engineered living microbial vectors harboring constructs encoding synthetic arrays of tumor-specific neoantigens that specifically colonize tumors following intravenous injection and deliver high levels of neoantigen cargo—both extracellularly (within the tumor microenvironment) and intracellularly (to the cytosol of tumor-resident phagocytes). These engineered vectors robustly activate innate immune cascades and effectively prime tumor neoantigen-directed T cell responses to promote tumor regression and survival in advanced murine solid tumor and lung metastasis models. Extensive remodeling of the tumor immune microenvironment accompanies therapeutic efficacy, with increased activation of tumor neoantigen-specific CD4+ and CD8+ T cells, broadened stimulation of tumor-infiltrating B and T cells, and reduced numbers of intratumoral myeloid cells exhibiting immunosuppressive phenotypes. This work provides a foundational platform for the development of a new class of next-generation tumor vaccines, leveraging the advantages of living medicines to deliver diverse arrays of tumor-specific neoantigens within the optimal immunostimulatory context to induce potent anti-tumor immunity. Citation Format: Andrew A. Redenti, Tal Danino, Nicholas Arpaia. Microbial neoantigen vectors for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3466.