Tumor Types Research Articles

Endoscopic ultrasound-guided bite-on-bite biopsy and endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of gastric tumors with negative malignant endoscopy biopsies: a retrospective cohort study.

Specific types of gastric tumors, including gastric linitis plastica and lymphoma, may cause extensive deep-layer infiltration, impeding an accurate diagnosis with endoscopic biopsy. This study aims to evaluate the efficacy of endoscopic ultrasound (EUS)-guided bite-on-bite biopsy and EUS-guided fine-needle aspiration (EUS-FNA) in diagnosing gastric malignancies with negative endoscopic biopsies. We retrospectively analyzed suspicious malignant gastric lesion cases in our hospital from October 2017 to August 2023. Clinical manifestations, radiographical examinations, endoscopic examinations, histopathological results, and therapeutic strategies were recorded and analyzed. Forty malignant gastric tumor cases with negative endoscopic biopsies were incorporated into our study. EUS-guided bite-on-bite biopsy was performed in 16 cases exclusively, whereas 17 patients received EUS-FNA exclusively, and seven patients underwent both simultaneously. Among the 23 patients who received the EUS-guided bite-on-bite biopsy, 22 (95.7%) were diagnosed with malignancies. Among the 24 patients who received EUS-FNA, a total of 19 cases with malignancies (79.2%) were confirmed by EUS-FNA (p = 0.11): 13 gastric adenocarcinomas, five metastatic malignancies, and one malignant stromal tumor. No adverse events were observed in any of the cases. EUS-guided bite-on-bite biopsy and EUS-FNA possess their advantages and disadvantages. EUS-guided bite-on-bite biopsy could serve as a reliable diagnostic method for shallow lesions with negative malignant endoscopic biopsies.

Failure of immune checkpoint inhibitors for microsatellite instability-positive pancreatic adenocarcinoma with atypical pattern of short tandem repeat mutation.

Microsatellite instability (MSI) is an important biomarker in cancer. While routine methods can detect MSI in certain tumor types, in other tumor types the results may be incorrect due to differences in the MSI loci pattern. Here, we report the case of a patient with pancreatic adenocarcinoma, with confirmed MSI by two independent next-generation sequencing tests, but not by routine methods, who had progression on pembrolizumab. Comparison of the patient's MSI loci patterns with MSI+ colorectal adenocarcinoma samples showed a lower fraction of unstable loci, low resolution of a second peak in the repeat length spectrum of unstable short tandem repeats in the patient's sample, and a lower length of indels (3.7 vs 4.5 base pairs, p<0.01).

A first-in-human phase I clinical study with MVX-ONCO-1, a personalized active immunotherapy, in patients with advanced solid tumors.

Purpose Over two decades, most cancer vaccines failed clinical development. Key factors may be the lack of efficient priming with tumor-specific antigens and strong immunostimulatory signals. MVX-ONCO-1, a personalized cell-based cancer immunotherapy, addresses these critical steps utilizing clinical-grade material to replicate a successful combination seen in experimental models: inactivated patient's own tumor cells, providing the widest cancer-specific antigens repertoire and a standardized, sustained, local delivery over days of a potent adjuvant achieved by encapsulated cell technology. Experimental Design We conducted an open-label, single-arm, first-in-human, phase I study with MVX-ONCO-1 in advanced refractory solid cancer patients. MVX-ONCO-1 comprises irradiated autologous tumor cells co-implanted with two macrocapsules containing genetically engineered cells producing granulocyte macrophage stimulating factor (GM-CSF). Patients received six immunizations over nine weeks without maintenance therapy. Primary objectives were safety, tolerability, and feasibility, while secondary objectives focused on efficacy and immune monitoring. Results Data from 34 patients demonstrated safety and feasibility with minor issues. Adverse events included one serious event (SAE) possibly related to investigational medicinal product (IMP), and two moderate-related adverse events (AE). Over 50% of patients with advanced and mainly non-immunogenic tumors showed clinical benefits, including partial responses (PR), stable diseases (SD), and prolonged survival. In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), one patient achieved a PR, while another survived for more than 7 years without anticancer therapy for over 5 years. Conclusion/Discussion MVX-ONCO-1 is safe, well-tolerated, and beneficial across several tumor types. Ongoing phase IIa trials target advanced R/M HNSCC patients post initial systemic therapy.

The recruitment of CD8+ T cells through YBX1 stabilization abrogates tumor intrinsic oncogenic role of MIR155HG in lung adenocarcinoma

Previous studies revealed that MIR155HG possessed an oncogenic role in many types of tumors including lung adenocarcinoma (LUAD), along with higher expression in tumors. However, in our study, we observed a positive correlation between MIR155HG expression and overall survival across different cohorts. The transferred PBMC on the NCG mouse model abrogated the tumor intrinsic oncogenic role of MIR155HG in LUAD. Upregulation of MIR155HG positively correlated with CD8+ T cell infiltration both in vitro and in vivo, as well as LUAD tissues. Mechanistically, we revealed that MIR155HG increased the cytokine CCL5 expression at the transcriptional level, which depended on the interaction between MIR155HG and YBX1 protein, a novel transcription factor of CCL5, resulting in the more protein stability of YBX1 through dampening ubiquitination. Additionally, we also observed that MIR155 could increase PD-L1 expression to hamper the activity of recruited CD8+ T cells, which could be rescued through PD-L1 mAb addition. Finally, we uncovered that patients with high MIR155HG expression had a higher response rate to immunotherapy, and the combination of MIR155HG overexpression and PD-L1 mAb increased the efficacy of PD-L1 mAb. Together, our study provides a novel biomarker and potential combination treatment strategy for patients who received immunotherapy.

Are bone targeted agents still useful in times of immunotherapy? The SAKK 80/19 BTA pilot study

BackgroundPatients with bone metastases from solid tumors often have additional treatment with bone targeted agents (BTAs) to avoid symptomatic skeletal events (SSEs) such as clinically significant pathological fracture leading toradiation therapy or surgery to the bone, spinal cord compression, or hypercalcemia. The absolute value of BTA treatment in the era of immunotherapy (IO) is unknown. MethodsPatients with bone metastases treated with immunotherapy within the Alpine Tumor Immunology Registry were compared based on whether they received an additional BTA such as denosumab or zoledronic acid. The primary endpoint was time to first SSE. Continuous data were summarized as median and range, categorical data using frequency counts and percentages. Kaplan-Meier estimates were used to describe and visualize the effect of categorical variables. ResultsOne hundred and ninety-seven patients with bone metastases and treatment with immunotherapy such as nivolumab (48 %), pembrolizumab (40 %), atezolizumab (12 %), ipilimumab (9 %) and other immunotherapy (5 %) were included. The most frequent tumor types were lung cancer (50 %), malignant melanoma (11 %), renal cell cancer (10 %) and bladder cancer (9 %), respectively. One hundred and twenty-two patients (62 %) received a BTA treatment (91 % denosumab). The median treatment duration of a BTA was 178 days (min: 1 day, max: 2010 days). Out of the 197 patients, 47 (24 %) experienced at least one SSE, 100 (51 %) had bone pain. Ten of the 122 patients (8 %) receiving a BTA developed osteonecrosis of the jaw (ONJ). The percentage of patients without an SSE at fixed time points was higher if treated with a BTA (e.g., at 6 months, 92 % [95 % CI: 84 % - 96 %] versus 88 % [95 % CI: 77 % - 94 %]), but no significant difference in time to first SSE (HR 0.69; 95 % CI 0.34–1.39, log-rank p = 0.29) or time to first bone pain (HR: 0.85; 95 % CI: 0.51–1.43, p = 0.54) between these two groups could be detected. There were differences in OS between patients treated with a BTA and patients not treated with a BTA (HR: 1.46; 95 % CI: 1.01–2.10, p = 0.043). ConclusionNo significant difference in time to first SSE or bone pain was observed between patients who have received a BTA or not when treated with immunotherapy. Based on these retrospective results the indication of BTAs to reduce SSEs in cancer patients under treatment with immunotherapy needs further evaluation.

RhIL-7-hyFc, a long-acting interleukin-7, improves efficacy of CAR-T cell therapy in solid tumors

BackgroundChimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable remission in patients with B-cell malignancies. However, its efficacy in treating solid tumors remains limited. Here, we investigated a combination therapy...

SPP1 could be an immunological and prognostic biomarker: From pan-cancer comprehensive analysis to osteosarcoma validation.

Secreted phosphoprotein 1 (SPP1), also known as osteopontin, is a phosphorylated protein. High SPP1 expression levels have been detected in multiple cancers and are associated with poor prognosis and reduced survival rates. However, only a few pan-cancer analyses have targeted SPP1. We conducted a comprehensive analysis using multiple public databases, including TIMER and TCGA, to investigate the expression levels of SPP1 in 33 different tumor types. In addition, we verified the effect of SPP1 on osteosarcoma. To assess the impact of SPP1 on patient outcomes, we employed univariate Cox regression and Kaplan-Meier survival analyses to analyze overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in these tumor patients. We also explored SPP1 gene alterations in various tumor tissues using cBioPortal. We then examined the relationship between SPP1 and clinical characteristics, TME, immune regulatory genes, immune checkpoints, TMB, and MSI using R language. In addition, we used GSEA to investigate the molecular mechanisms underlying the role of SPP1. Bioinformatics analysis indicated that SPP1 was upregulated in 17 tumors. Overexpression of SPP1 results in poor OS, DSS, and PFI in CESC, ESCA, GBM, LGG, LIHC, PAAD, PRAD, and skin cutaneous melanoma. SPP1 expression was positively associated with immunocyte infiltration, immune regulatory genes, immune checkpoints, TMB, MSI, and drug sensitivity in certain cancers. We found that high expression of SPP1 in osteosarcoma was related to drug resistance and metastasis and further demonstrated that SPP1 can stimulate osteosarcoma cell proliferation via CCND1 by activating the PI3K/Akt pathway. These findings strongly suggest that SPP1 is a potential prognostic marker and novel target for cancer immunotherapy.

HER2-targeted therapies beyond breast cancer - an update.

The receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification. These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities. These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes.

Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations

Cancer driver genes can undergo positive selection for various types of genetic alterations, including gain-of-function or loss-of-function mutations and copy number alterations (CNA). We investigated the landscape of different types of alterations affecting driver genes in 17,644 cancer exomes and genomes. We find that oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments, suggesting a method to identify additional tumor types where an oncogene is a driver or a vulnerability. Next, we characterize the landscape of CNA-dependent selection effects, revealing a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. Similarly, we observe a positive interaction between mutations and CNA gains in tumor suppressor genes. Thus, two-hit events involving point mutations and CNA are universally observed regardless of the type of CNA and may signal new therapeutic opportunities. An analysis with focus on the somatic CNA two-hit events can help identify additional driver genes relevant to a tumor type. By a global inference of point mutation and CNA selection signatures and interactions thereof across genes and tissues, we identify 9 evolutionary archetypes of driver genes, representing different mechanisms of (in)activation by genetic alterations.

Synergistic effects of PARP inhibition and cholesterol biosynthesis pathway modulation.

An in-depth multi-omic molecular characterisation of poly(adenosine 5'-diphosphate [ADP]-ribose) polymerase (PARP) inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula®) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signalling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of a LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing of cancer cells to levels comparable to Niraparib as single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of HMGCR, an enzyme catalysing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism.

Do tunneling nanotubes drive chemoresistance in solid tumors and other malignancies?

Intercellular communication within the tumor microenvironment (TME) is essential for establishing, mediating, and synchronizing cancer cell invasion and metastasis. Cancer cells, individually and collectively, react at the cellular and molecular levels to insults from standard-of-care treatments used to treat patients with cancer. One form of cell communication that serves as a prime example of cellular phenotypic stress response is a type of cellular protrusion called tunneling nanotubes (TNTs). TNTs are ultrafine, actin-enriched contact-dependent forms of membrane protrusions that facilitate long distance cell communication through transfer of various cargo, including genetic materials, mitochondria, proteins, ions, and various other molecules. In the past 5-10 years, there has been a growing body of evidence that implicates TNTs as a novel mechanism of cell-cell communication in cancer that facilitates and propagates factors that drive or enhance chemotherapeutic resistance in a variety of cancer cell types. Notably, recent literature has highlighted the potential of TNTs to serve as cellular conduits and mediators of drug and nanoparticle delivery. Given that TNTs have also been shown to form in vivo in a variety of tumor types, disrupting TNT communication within the TME provides a novel strategy for enhancing the cytotoxic effect of existing chemotherapies while suppressing this form of cellular stress response. In this review, we examine current understanding of interplay between cancer cells occurring via TNTs, and even further, the implications of TNT-mediated tumor-stromal cross-talk and the potential to enhance chemoresistance. We then examine tumor microtubes, an analogous cell protrusion heavily implicated in mediating treatment resistance in glioblastoma multiforme, and end with a brief discussion of the effects of radiation and other emerging treatment modalities on TNT formation.

Brain Tumors in Pediatric Patients

Pediatric brain tumors are the most common solid tumors in children, comprising a diverse group of neoplasms that vary in histology, location, and behavior. Common types include astrocytomas, medulloblastomas, ependymomas, and brainstem gliomas. Symptoms often depend on the tumor's location and may include headaches, nausea, vomiting, balance issues, and cognitive or behavioral changes. Advances in imaging, surgical techniques, and therapies, including radiation and chemotherapy, have improved outcomes. However, treatment can have long-term effects on cognitive and physical development, making comprehensive care and follow-up essential for pediatric patients. Early published reviews on pediatric brain tumors may have several lacunae, such as limited data on long-term outcomes, emerging treatment modalities, and the genetic and molecular underpinnings of various tumor types. They might also inadequately address the psychosocial impacts on patients and families. Therefore, a comprehensive review is needed to synthesize the latest research on pediatric brain tumors, encompassing advancements in diagnosis, treatment, and survivorship care. This updated review will provide valuable insights for clinicians, researchers, and policymakers to improve managing and supporting children with brain tumors. The review covers various aspects of pediatric brain tumors, focusing on choroid plexus tumors and spinal cord tumors. It discusses treatment strategies, highlighting surgical, radiotherapy, and chemotherapy options. The review also details presenting signs and symptoms of brain tumors in children, such as headaches, nausea, vomiting, balance issues, and changes in behavior or cognition. These insights aim to enhance early diagnosis and effective management, improving outcomes for affected children. This review addresses gaps in earlier studies on pediatric brain tumors by providing comprehensive insights into choroid plexus and spinal cord tumors, updated treatment strategies, and detailed symptoms. It synthesizes recent research to enhance early diagnosis and management, meeting current needs for effective, tailored treatment and improving patient outcomes.

Real-world genetic testing outcomes of pan-cancer testing for mismatch repair deficiency.

In 2017, the Food and Drug Administration approved pembrolizumab for treatment of any mismatch repair-deficient (dMMR) tumor making MMR immunohistochemistry (IHC) testing beneficial for all tumor types. For the first time, MMR IHC was not performed exclusively to screen for Lynch syndrome (LS). In this study, all MMR IHC reports issued between 2017 and 2021 at an academic hospital were reviewed and completion of genetic testing was determined through chart review. Colorectal cancers (CRCs), endometrial cancers (ECs), and noncancerous lesions were excluded. Between 2017 and 2021, MMR IHC was completed in 1939 patients with a malignancy other than CRC or EC. Absent or weak staining for at least one MMR protein was detected in 115 (5.9%) patients and 59 (51%) of those completed germline genetic testing. Overall, the identification rate of LS in this cohort was 0.72%, which is similar to the rate in our previously reported CRC and EC universal screening cohort. A diagnosis of LS was most commonly made in patients with dMMR brain (18.75%) and small intestinal cancers (10.20%). Five additional patients were found to carry a pathogenic variant in a non-LS gene. Pan-cancer MMR testing for pembrolizumab consideration can identify LS cases at a rate similar to universal CRC and EC screening programs. A persistent challenge is subsequent uptake of genetic testing. MMR testing should be prioritized in brain and small intestinal tumors, and multigene panel testing is recommended in patients with dMMR, as unexpected pathogenic variants in non-LS genes were found as frequently as LS gene variants.

Hotspot Exon 15 Mutations in BRAF Are Uncommon in Feline Tumours.

BRAF is one of multiple RAF proteins responsible for the activation of the MAPK cell signalling cascade involved in cell growth, differentiation, and survival. A hotspot BRAFV600E mutation, in exon 15, was determined to be a driver in 100% hairy cell leukaemias, 50%-60% of human melanomas, 30%-50% of human thyroid carcinomas and 10%-20% of human colorectal carcinomas. The orthologous BRAFV595E mutation was seen in 67% and 80% of canine bladder transitional cell carcinomas and prostatic adenocarcinomas, respectively. Since veterinary and human cancers exploit similar pathways and BRAF is highly conserved across species, BRAF can be expected to be a driver in a feline cancer. Primers were developed to amplify exon 15 of feline BRAF. One hundred ninety-six feline tumours were analysed. Sanger sequencing of the 211 bp PCR amplicon was done. A BRAF mutation was found in one tumour, a cutaneous melanoma. The mutation was a BRAFV597E mutation, orthologous to the canine and human hotspot mutations. A common synonymous variant, BRAFT586T, was seen in 23% (47/196) of tumours. This variant was suspected to be a single nucleotide polymorphism. BRAF was not frequently mutated in common feline tumours or in tumour types that frequently harbour BRAF mutations in human and canine cancers. As is seen in canine cancer genomics, the mutational profile in feline tumours may not parallel the histologic equivalent in human oncology.

A Multi-Center, Multi-Parametric MRI Dataset of Primary and Secondary Brain Tumors

Brain metastases (BMs) and high-grade gliomas (HGGs) are the most common and aggressive types of malignant brain tumors in adults, with often poor prognosis and short survival. As their clinical symptoms and image appearances on conventional magnetic resonance imaging (MRI) can be astonishingly similar, their accurate differentiation based solely on clinical and radiological information can be very challenging, particularly for “cancer of unknown primary”, where no systemic malignancy is known or found. Non-invasive multiparametric MRI and radiomics offer the potential to identify these distinct biological properties, aiding in the characterization and differentiation of HGGs and BMs. However, there is a scarcity of publicly available multi-origin brain tumor imaging data for tumor characterization. In this paper, we introduce a multi-center, multi-origin brain tumor MRI (MOTUM) imaging dataset obtained from 67 patients: 29 with high-grade gliomas, 20 with lung metastases, 10 with breast metastases, 2 with gastric metastasis, 4 with ovarian metastasis, and 2 with melanoma metastasis. This dataset includes anonymized DICOM files alongside processed FLAIR, T1-weighted, contrast-enhanced T1-weighted, T2-weighted sequences images, segmentation masks of two tumor regions, and clinical data. Our data-sharing initiative is to support the benchmarking of automated tumor segmentation, multi-modal machine learning, and disease differentiation of multi-origin brain tumors in a multi-center setting.

The landscape of cancer-associated transcript fusions in adult brain tumors: a longitudinal assessment in 140 patients with cerebral gliomas and brain metastases

BackgroundOncogenic fusions of neurotrophic receptor tyrosine kinase NTRK1, NTRK2, or NTRK3 genes have been found in different types of solid tumors. The treatment of patients with TRK fusion cancer with a first-generation TRK inhibitor (such as larotrectinib or entrectinib) is associated with high response rates (&amp;gt;75%), regardless of tumor histology and presence of metastases. Due to the efficacy of TRK inhibitor therapy of larotrectinib and entrectinib, it is clinically important to identify patients accurately and efficiently with TRK fusion cancer. In this retrospective study, we provide unique data on the incidence of oncogenic NTRK gene fusions in patients with brain metastases (BM) and gliomas.Methods140 samples fixed and paraffin-embedded tissue (FFPE) of adult patients (59 of gliomas [17 of WHO grade II, 20 of WHO grade III and 22 glioblastomas] and 81 of brain metastasis (BM) of different primary tumors) are analyzed. Identification of NTRK gene fusions is performed using next-generation sequencing (NGS) technology using Focus RNA assay kit (Thermo Fisher Scientific).ResultsWe identified an ETV6 (5)::NTRK3 (15) fusion event using targeted next-generation sequencing (NGS) in one of 59 glioma patient with oligodendroglioma–grade II, IDH-mutated and 1p19q co-deleted at incidence of 1.69%. Five additional patients harboring TMPRSS (2)::ERG (4) were identified in pancreatic carcinoma brain metastasis (BM), prostatic carcinoma BM, endometrium BM and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted. A FGFR3 (17)::TACC3 (11) fusion was identified in one carcinoma breast BM. Aberrant splicing to produce EGFR exons 2-7 skipping mRNA, and MET exon 14 skipping mRNA were identified in glioblastoma and pancreas carcinoma BM, respectively.ConclusionsThis study provides data on the incidence of NTRK gene fusions in brain tumors, which could strongly support the relevance of innovative clinical trials with specific targeted therapies (larotrectinib, entrectinib) in this population of patients. FGFR3 (17)::TACC3 (11) rearrangement was detected in breast carcinoma BM with the possibility of using some specific targeted therapies and TMPRSS (2)::ERG (4) rearrangements occur in a subset of patients with, prostatic carcinoma BM, endometrium BM, and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted, where there are yet no approved ERG-directed therapies.

Efficacy and safety evaluation of cross-reactive Fibroblast activation protein scFv-based CAR-T cells

IntroductionFibroblast activation protein (FAP) overexpression on cancer-associated fibroblasts (CAFs) is associated with poor prognosis and worse clinical outcomes. Selective ablation of pro-tumorgenic FAP+ stromal cells with CAR-T cells may be a new therapeutic strategy. However, the clinical use of FAP-CAR T cells is suggested to proceed with caution for occasional poor efficacy and induction of on-target off-tumor toxicity (OTOT), including lethal osteotoxicity and cachexia. Hence, more investigations and preclinical trials are required to optimize the FAP-CAR T cells and to approve their safety and efficacy.MethodsIn this study, we designed second-generation CAR T cells targeting FAP with 4-1BB as a co-stimulatory molecule, and tested their cytotoxicity against FAP-positive cells (hFAP-HT1080 cells and a variety of primary CAFs) in vitro and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model.ResultsResults showed that our FAP-CAR T cells were powerfully potent in killing human and murine FAP-positive tumor cells and CAFs in multiple types of tumors in BALB/c and C57BL/6 mice and in patient-derived xenografts (PDX) model. And they were proved to be biologically safe and exhibit low-level OTOT.DiscussionTaken together, the human/murine cross-reactive FAP-CAR T cells were powerfully potent in killing human and murine FAP positive tumor cells and CAFs. They were biologically safe and exhibit low-level OTOT, warranting further clinical investigation into our FAP-CAR T cells.

Characterization of latently infected EBV+ antibody-secreting B cells isolated from ovarian tumors and malignant ascites

IntroductionIntra-tumoral B cells mediate a plethora of immune effector mechanisms with key roles in anti-tumor immunity and serve as positive prognostic indicators in a variety of solid tumor types, including epithelial ovarian cancer (EOC). Several aspects of intra-tumoral B cells remain unclear, such as their state of activation, antigenic repertoires, and capacity to mature into plasma cells.MethodsB lymphocytes were isolated from primary EOC tissue and malignant ascites and were maintained in cell culture medium. The stably maintained cell lines were profiled with flow cytometry and B cell receptor sequencing. Secreted antibodies were tested with a human proteome array comprising more than 21,000 proteins, followed by ELISA for validation. Originating tumor samples were used for spatial profiling with chip cytometry.ResultsAntibody-secreting B lymphocytes were isolated from the ovarian tumor microenvironment (TME) of four different EOC patients. The highly clonal cell populations underwent spontaneous immortalization in vitro, were stably maintained in an antibody-secreting state, and showed presence of Epstein-Barr viral (EBV) proteins. All originating tumors had high frequency of tumor-infiltrating B cells, present as lymphoid aggregates, or tertiary lymphoid structures. The antigens recognized by three of the four cell lines are coil-coil domain containing protein 155 (CCDC155), growth factor receptor-bound protein 2 (GRB2), and pyruvate dehydrogenase phosphatase2 (PDP2), respectively. Anti-CCDC155 circulating IgG antibodies were detected in 9 of 20 (45%) of EOC patients’ sera. Tissue analyses with multiparameter chip cytometry shows that the antibodies secreted by these novel human B cell lines engage their cognate antigens on tumor cells.DiscussionThese studies demonstrate that within the tumor-infiltrating lymphocyte population in EOC resides a low frequency population of antibody-secreting B cells that have been naturally exposed to EBV. Once stably maintained, these novel cell lines offer unique opportunities for future studies on intratumor B cell biology and new target antigen recognition, and for studies on EBV latency and/or viral reactivation in the TME of non-EBV related solid tumors such as the EOC.

Prevalence of homologous recombination biomarkers in multiple tumor types: an observational study.

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6-34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

Comprehensive landscape of m6A regulator-related gene patterns and tumor microenvironment infiltration characterization in gastric cancer

The epigenetic regulation of N6-methyladenosine (m6A) has attracted considerable interest in tumor research, but the potential roles of m6A regulator-related genes, remain largely unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 m6A regulators (including novel anti-readers) was employed to identify m6A regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct m6A regulator-related patterns were identified through the unsupervised clustering of 56 m6A regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an m6A-related scoring system was developed to quantify the m6A modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the m6A-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of m6A regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.