Biology subjects

Wu, C.

Publications and source records attributed to Wu, C..

At least 217 records · Page 12Linked to original sources

bioRxiv2022

PP4 inhibition sensitizes ovarian cancer to NK cell-mediated cytotoxicity via STAT1 activation and inflammatory signaling

BackgroundIncreased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in ovarian cancer (OC), the frequency of responses to immune checkpoint blockade (ICB) therapy in OC is much lower than other cancer types. Recent studies have highlighted that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity, which leads to enhanced responses to ICB. Protein phosphatase 4 (PP4) is a critical regulator of the DDR; however, its potential role in anti-tumor immunity is currently unknown. ResultsOur results show that the PP4 inhibitor, fostriecin, combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using multiple ovarian cancer cell lines, we show that PP4 inhibition or PPP4C knockdown combined with carboplatin triggers inflammatory signaling via NF{kappa}B and STAT1 activation. This resulted in increased expression of the pro-inflammatory cytokines and chemokines: CCL5, CXCL10, and IL6. In addition, IFNB1 expression was increased suggesting activation of the type I interferon response. Conditioned media from OC cells treated with the combination of PP4 inhibitor and carboplatin significantly increased migration of both CD8 T cell and NK cells over carboplatin treatment alone. Knockdown of STING in OC cells significantly abrogated the increase in CD8 T cell migration induced by PP4 inhibition. Co-culture of NK-92 cells and OC cells with PPP4C or PPP4R3B knockdown resulted in strong induction of NK cell activation as measured by IFN-{gamma} levels. Further, we also observed increased degranulation and NK cell-mediated cytotoxicity against OC cells with PPP4C or PPP4R3B knockdown. ConclusionsOur work has identified a role for PP4 inhibition in promoting inflammatory signaling and enhanced immune cell effector function. These findings support the further investigation of PP4 inhibitors to enhance chemo-immunotherapy for ovarian cancer treatment.

cancer biology↗

bioRxiv2022

Oncogenic EFNA4 amplification promotes lung adenocarcinoma lymph node metastasis

Lymph nodes metastases are common in patients with lung cancer. And those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. So-matic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are a major type of DNA alteration that promotes lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung cancer metastasis related gene, EFNA4. EFNA4 genome locus was significantly amplified and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 over-expression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis and suggests EFNA4 as a potential target in metastatic lung cancer therapy. Simple SummaryLymph nodes are likely to be the first stop for lung cancer metastasis. To further investigate the mechanism of lung cancer lymph node metastasis, we performed cancer genome analysis and found that EFNA4, a member of the ephrin (EPH) family, is amplified and up-regulated in lung tumor patients, especially in patients with lymph node metastases. In vitro and in vivo experiments show that overexpression of EFNA4 promotes lung tumor cell proliferation and migration, while knockdown or knockout of EFNA4 inhibits cell proliferation and migration. Altogether, our results suggest that the DNA amplification of EFNA4 genome locus could play an oncogenic function in promoting lung cancer lymph node metastasis.

cancer biology↗

bioRxiv2022

Development of Equine Polyclonal Antibodies as a Broad-Spectrum Therapy Against SARS-CoV-2 Variants

The Coronavirus disease 19 (COVID-19) pandemic has accumulated over 550 million confirmed cases and more than 6.34 million deaths worldwide. Although vaccinations has largely protected the population through the last two years, the effect of vaccination has been increasingly challenged by the emerging SARS-CoV-2 variants. Although several therapeutics including both monoclonal antibodies and small molecule drugs have been used clinically, high cost, viral escape mutations, and potential side effects have reduced their efficacy. There is an urgent need to develop a low cost treatment with wide-spectrum effect against the novel variants of SARS-CoV-2. Here we report a product of equine polyclonal antibodies that showed potential broad spectrum neutralization effect against the major variants of SARS-CoV-2. The equine polyclonal antibodies were generated by horse immunization with the receptor binding domain (RBD) of SARS-CoV-2 spike protein and purified from equine serum. A high binding affinity between the generated equine antibodies and the RBD was observed. Although designed against the RBD of the early wild type strain sequenced in 2020, the equine antibodies also showed a highly efficient neutralization capacity against the major variants of SARS-CoV-2, including the recent BA.2 Omicron variant (IC50 =1.867g/ml) in viral neutralization assay in Vero E6 cells using live virus cultured. The broad-spectrum neutralization capacity of the equine antibodies was further confirmed using pseudovirus neutralization assay covering the major SARS-CoV-2 variants including wild type, alpha, beta, delta, and omicron, showing effective neutralization against all the tested strains. Ex vivo reconstructed human respiratory organoids representing nasal, bronchial, and lung epitheliums were employed to test the treatment efficacy of the equine antibodies. Antibody treatment protected the human nasal, bronchial, and lung epithelial organoids against infection of the novel SARS-CoV-2 variants challenging public health, the Delta and Omicron BA.2 isolates, by reducing >95% of the viral load. The equine antibodies were further tested for potential side effects in a mouse model by inhalation and no significant pathological feature was observed. Equine antibodies, as a mature medical product, have been widely applied in the treatment of infectious diseases for more than a century, which limits the potential side effects and are capable of large scale production at a low cost. A cost-effective, wide-spectrum equine antibody therapy effective against the major SARS-CoV-2 variants can contribute as an affordable therapy to cover a large portion of the world population, and thus potentially reduce the transmission and mutation of SARS-CoV-2.

immunology↗

bioRxiv2022

SiPLATZ12 transcript factor regulates multiple yield traits and salt tolerance in foxtail millet (Setaria italica)

Grain yield and salt tolerance are critical for crop production. However, the genetic and biochemical basis underlying the trade-off of these characters remain poorly described in crops. We show here that SiPLATZ12 transcription factor positively regulates multiple elite yield traits at the expense of salt tolerance in foxtail millet. SiPLATZ12 overexpression increases seed size, panicle length, and stem diameter, while reduces plant height and salt tolerance of foxtail millet. A 9-bp insertion in the SiPLATZ12 promoter has significant effects on the different expression of SiPLATZ12, multiple yield traits, and salt tolerance between foxtail millet and its wild ancestor, green foxtail. Moreover, SiPLATZ12 upregulates the expression of genes involved in seed development, but repressing the transcription of most NHX, SOS, and CBL genes to regulate Na+, K+ and pH homeostasis. Therefore, our results uncover a domesticated site that could be used to improve grain yield and salt tolerance in foxtail millet.

molecular biology↗

bioRxiv2022

Rab7/Retromer-based endolysosomal trafficking facilitates effector secretion and host invasion in rice blast

Secretion is a fundamental process in all living organisms. Using conventional secretion pathways, many plant pathogens release effectors into the host plants to downregulate immunity and promote infection. However, this does not always constitute the only way that effectors are sorted and tracked to their final destination such as the biotrophic interfacial complex-associated effectors produced by the blast fungus Magnaporthe oryzae. Here, we uncover a novel unconventional route originating from fungal vacuolar membrane to the host interface and plasma membrane. We found that a GFP-MoRab7 labeled vacuole is closely associated with the interface structure throughout M. oryzae invasive growth. Conditional inactivation of MoRab7 impaired the establishment of the biotrophy interface and secretion of Pwl2 effector. To perform the vacuolar trafficking pathway, MoRab7 first recruits the retromer complex to the vacuole membrane, enabling it recognizes a batch of SNARE proteins, including the v-SNARE MoSnc1. Live-cell imaging supports both retromer complex component and MoSnc1 protein labeled vesicles showing the trafficking dynamics toward the interface or plasma membrane, and then fusion with target membranes. Lastly, disruption of the MoRab7/Retromer/MoSnc1-based endolysosomal cascade affects effector secretion and fungal pathogenicity. Taken together, we discovered an unconventional protein and membrane trafficking route starting from the fungal endolysosomes to the M. oryzae-rice interaction interface, and dissect the role of MoRab7/Retromer/MoSnc1 constituent sorting machinery in effector secretion during invasive growth in M. oryzae.

plant biology↗

bioRxiv2022

Abl2 mediates microtubule nucleation and repair via tubulin co-condensation.

Abl family kinases are evolutionarily conserved regulators of cell migration and morphogenesis. Genetic experiments in Drosophila suggest that Abl family kinases interact functionally with microtubules to regulate axon guidance and neuronal morphogenesis. Vertebrate Abl2 binds to microtubules and promotes their plus-end elongation both in vitro and in cells, but the molecular mechanisms by which Abl2 regulates microtubule (MT) dynamics were unclear. We report here that Abl2 regulates MT assembly via condensation and direct interactions with both the MT lattice and tubulin dimers. We find that Abl2 promotes MT nucleation, which is further facilitated by the ability of the Abl2 C-terminal half to undergo phase separation and form co-condensates with tubulin. A naturally occurring tubulin binding-deficient Abl2 splice isoform fails to promote nucleation. Abl2 binds to regions adjacent to MT damage and facilitates their repair via fresh tubulin recruitment and increases MT rescue frequency and lifetime. MT recovery after nocodazole treatment is greatly slowed in Abl2 knockout COS-7 cells compared to wild type cells. We propose a model in which Abl2 locally concentrates tubulin and recruits it to MT tips or to defects in the MT lattice to promote MT repair, rescue, and nucleation.

biochemistry↗

bioRxiv2022

Optimizing CpG spatial distribution with DNA origami for Th1-polarized therapeutic vaccination

Multivalent presentation of ligands often enhances receptor activation and downstream signaling. DNA origami offers precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we introduce a "square block" DNA origami platform to explore the importance of spacing of CpG oligonucleotides, which engage Toll-like receptors and thereby act as danger signals for dendritic cells. Through in vitro cell-culture studies and in vivo tumor-treatment models, we demonstrate that square blocks induce Th1 immune polarization when CpG is spaced at 3.5 nm. We observe that this DNA origami vaccine enhances DC activation, antigen cross-presentation, CD8 T cell activation, Th1-polarized CD4 activation and NK cell activation. The vaccine also synergizes effectively with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T cell memory. Our results suggest that DNA origami may serve as an advanced vaccine platform for controlling adjuvant spacing and co-delivering antigens. One Sentence SummaryThis study developed a DNA origami-based cancer vaccine (DoriVac) that co-delivers antigen and CpG immune adjuvant with an optimal nanospacing for Th1 immune polarization.

synthetic biology↗

bioRxiv2022

Screening the PRISM library against Staphylococcus aureus reveals a sesquiterpene lactone from Liriodendron tulipifera with inhibitory activity

Infections caused by the bacterium Staphylococcus aureus continue to pose threats to human health and put a financial burden on the healthcare system. The overuse of antibiotics has contributed to mutations leading to the emergence of methicillin-resistant Staphylococcus aureus, and there is a critical need for the discovery and development of new antibiotics to evade drug resistant bacteria. Medicinal plants have shown promise as sources of new small molecule therapeutics with potential uses against pathogenic infections. The Principal Rhode Island Secondary Metabolite (PRISM) library is a botanical extract library generated from specimens in the URI Heber W. Youngken Jr. Medicinal Garden by upper-division undergraduate students. PRISM extracts were screened for activity against strains of methicillin-susceptible S. aureus (MSSA). An extract generated from the tulip tree (Liriodendron tulipifera) demonstrated growth inhibition against MSSA, and a bioassay-guided approach identified a sesquiterpene lactone, laurenobiolide, as the active constituent. Intriguingly, its isomers tulipinolide and epi-tulipinolide lacked potent activity against MSSA. Laurenobiolide also proved to be more potent against MSSA than the structurally similar sesquiterpene lactones constunolide and dehydrocostus lactone. Laurenobioloide was most abundant in the twig bark of the tulip tree, supporting the historical and cultural usage of twig bark in poultices and teas. ABSTRACT GRAPHIC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/494747v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@952221org.highwire.dtl.DTLVardef@f3a5daorg.highwire.dtl.DTLVardef@d91daorg.highwire.dtl.DTLVardef@e2a845_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Inner hair cell synapse density influences auditory processing

Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy), leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.

neuroscience↗

bioRxiv2022

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.1 and BA.2 variants and their mouse origins

The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies reveal that the Omicron BA.2 spike trimer have 11-fold and 2-fold higher potency to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to have efficient inhibition of Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants from human-cat-mouse-human circle, which could have important implications in establishing an effective strategy in combating viral infection.

biophysics↗

bioRxiv2022

Pan-cancer quantification of neoantigen-mediated immunoediting in cancer evolution

Immunoediting, which includes three temporally distinct stages, termed elimination, equilibrium, and escape, has been proposed to explain the interactions between cancer cells and the immune system during the evolution of cancer. However the status of immunoediting in cancer remains unclear, and the existence of neoantigen depletion signal in untreated cancer has been debated. Here we developed a distribution pattern based method for quantifying neoantigen mediated negative selection in cancer evolution. Our method provides a robust and reliable quantification for immunoediting signal in an individual cancer patient. The prevalence of immunoediting signal in immunotherapy untreated cancer genome has been demonstrated with this method. Importantly, the elimination and escape stages of immunoediting can be quantified separately, tumor types with strong immunoediting-elimination tend to have weak immunoediting-escape signal, and vice versa. Quantified immunoediting-elimination signal predicts cancer immunotherapy clinical response. Immunoediting quantification provides an evolutional perspective for evaluating the antigenicity of neoantigen, and reveals a potential biomarker for cancer precision immunotherapy.

cancer biology↗

bioRxiv2022

A toolkit of highly selective and sensitive genetically encoded neuropeptide sensors

Neuropeptides are key signaling molecules in the endocrine and nervous systems that regulate many critical physiological processes, including energy balance, sleep and circadian rhythms, stress, and social behaviors. Understanding the functions of neuropeptides in vivo requires the ability to monitor their dynamics with high specificity, sensitivity, and spatiotemporal resolution; however, this has been hindered by the lack of direct, sensitive and non-invasive tools. Here, we developed a series of GRAB (G protein-coupled receptor activation-based) sensors for detecting somatostatin (SST), cholecystokinin (CCK), corticotropin-releasing factor (CRF), neuropeptide Y (NPY), neurotensin (NTS), and vasoactive intestinal peptide (VIP). These fluorescent sensors utilize the corresponding GPCRs as the neuropeptide-sensing module with the insertion of a circular-permutated GFP as the optical reporter. This design detects the binding of specific neuropeptides at nanomolar concentration with a robust increase in fluorescence. We used these GRAB neuropeptide sensors to measure the spatiotemporal dynamics of endogenous SST release in isolated pancreatic islets and to detect the release of both CCK and CRF in acute brain slices. Moreover, we detect endogenous CRF release induced by stressful experiences in vivo using fiber photometry and 2-photon imaging in mice. Together, these new sensors establish a robust toolkit for studying the release, function, and regulation of neuropeptides under both physiological and pathophysiological conditions.

neuroscience↗

bioRxiv2022

CryoET Reveals Organelle Phenotypes in Huntington Disease Patient iPSC-Derived and Mouse Primary Neurons

Huntingtons Disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. Patient-derived induced pluripotent stem cells (iPSCs) can help understand disease; however, defining pathological biomarkers is challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered mitochondria with enlarged granules and distorted cristae, and thin sheet aggregates in double membrane-bound organelles. We used artificial intelligence to quantify mitochondrial granules, and proteomics to show differential protein content in HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC-neurons and reduced phenotypes in BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

neuroscience↗

bioRxiv2022

A high-performance genetically encoded fluorescent indicator for in vivo cAMP imaging

cAMP is a key second messenger that regulates diverse cellular functions including neural plasticity. However, the spatiotemporal dynamics of intracellular cAMP in intact organisms are largely unknown due to low sensitivity and/or brightness of current genetically encoded fluorescent cAMP indicators. Here, we report the development of the new circularly permuted GFP (cpGFP)-based cAMP indicator G-Flamp1, which exhibits a large fluorescence increase (a maximum {Delta}F/F0 of 1100% in HEK293T cells), relatively high brightness, appropriate affinity (a Kd of 2.17 {micro}M) and fast response kinetics (an association and dissociation half-time of 0.20 s and 0.087 s, respectively). Furthermore, the crystal structure of the cAMP-bound G-Flamp1 reveals one linker connecting the cAMP-binding domain to cpGFP adopts a distorted {beta}-strand conformation that may serve as a fluorescence modulation switch. We demonstrate that G-Flamp1 enables sensitive monitoring of endogenous cAMP signals in brain regions that are implicated in learning and motor control in living organisms such as fruit flies and mice.

molecular biology↗

bioRxiv2022

An evolutionarily conserved mechanism for control the translation of long proteins

Plants have evolved sophisticated mechanisms to regulate gene expression to activate immune responses against pathogen infections. However, how the translation system contributes to plant immunity is largely unknown. The evolutionarily conserved thiolation modification of tRNA ensures efficient decoding during translation. Here we show that tRNA thiolation is required for plant immunity in Arabidopsis. We identify a cgb Arabidopsis mutant, which is hyper-susceptible to the pathogen Pseudomonas syringae. CGB encodes ROL5, a homolog of yeast NCS6 required for tRNA thiolation. ROL5 physically interacts with CTU2, a homolog of yeast NCS2. Mutations in either ROL5 or CTU2 result in loss of tRNA thiolation. Further analyses reveal that both transcriptional reprogramming and translational reprogramming during immune responses are compromised in cgb. Notably, the translation of the salicylic acid receptor NPR1 is reduced in cgb, resulting in reduced salicylic acid signaling. Our study not only reveals a new regulatory mechanism for plant immunity but also uncovers a new biological function of tRNA thiolation.

biochemistry↗

bioRxiv2022

A new immunocompetent rectal cancer model to study radiation therapy

We describe a new mouse model of rectal cancer (RC) involving rapid tumor organoid engraftment via orthotopic transplantation; the resulting RC tumors invaded inward from the mucosal surface and metastasized to distant organs. Histologically the tumors closely resemble human RC and mirror remodeling of the tumor microenvirnoment (TME) in response to radiation. This murine RC model thus recapitulates the pathogenesis of human RC, thereby fulfilling the need for a physiologically accurate model for preclinical efficacy studies.

cancer biology↗

bioRxiv2022

Vaccine Protection Against the SARS-CoV-2 Omicron Variant in Macaques

BackgroundThe rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. Immune correlates of vaccine protection against Omicron are not known. Methods30 cynomolgus macaques were immunized with homologous and heterologous prime-boost regimens with the mRNA-based BNT162b2 vaccine and the adenovirus vector-based Ad26.COV2.S vaccine. Following vaccination, animals were challenged with the SARS-CoV-2 Omicron variant by the intranasal and intratracheal routes. ResultsOmicron neutralizing antibodies were observed following the boost immunization and were higher in animals that received BNT162b2, whereas Omicron CD8+ T cell responses were higher in animals that received Ad26.COV2.S. Following Omicron challenge, sham controls showed more prolonged virus in nasal swabs than in bronchoalveolar lavage. Vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs, showing that current vaccines provide substantial protection against Omicron in this model. However, vaccinated animals that had moderate levels of Omicron neutralizing antibodies but negligible Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Virologic control correlated with both antibody and T cell responses. ConclusionsBNT162b2 and Ad26.COV2.S provided robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in macaques. Protection against this highly mutated SARS-CoV-2 variant correlated with both humoral and cellular immune responses.

microbiology↗

bioRxiv2022

Extrachromosomal DNA is associated with decreased immune cell infiltration and antigen presentation, represents a potential cancer immune evasion mechanism

Extrachromosomal DNA (ecDNA) is a type of circular and tumor specific genetic element. EcDNA has been reported to display open chromatin structure, facilitate oncogene amplification and genetic material unequal segregation, and is associated with poor cancer patients prognosis. The ability of immune evasion is a typical feature for cancer progression, however the tumor intrinsic factors that determine immune evasion remain poorly understood. Here we show that the presence of ecDNA is associated with markers of tumor immune evasion, and obtaining ecDNA could be one of the mechanisms employed by tumor cells to escape immune surveillance. Tumors with ecDNA usually have comparable TMB and neoantigen load, however they have lower immune cell infiltration and lower cytotoxic T cell activity. The microenvironment of tumors with ecDNA shows increased immune desert, decreased immune enriched fibrotic types. Both MHC class I and class II antigen presentation genes expression are decreased in tumors with ecDNA, and this could be the underlying mechanism for ecDNA associated immune evasion. This study provides evidence that the presence of ecDNA is an immune escape mechanism for cancer cells.

cancer biology↗