Biology subjects

Suresh, A.

Publications and source records attributed to Suresh, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Parvalbumin interneuron maturation reorganizes cortical population activity structure during development

During brain development, spontaneous cortical activity undergoes a dramatic transformation from highly synchronous network events to less correlated and sparse neuronal firing that is thought to underlie more flexible neural coding. However, how the structure of population activity changes across this transition, what circuit mechanisms drive this reorganization, and the implications for information encoding have not been fully established. Using longitudinal in vivo calcium imaging in early postnatal mice, we demonstrate that cortical network desynchronization during the second postnatal week is accompanied by a redistribution of fractional variance from dominant, low-dimensional modes into many weaker dimensions, and a growing influence of GABAergic interneurons (INs) on the network. All-optical circuit interrogation revealed that parvalbumin (PV) INs, but not somatostatin (SST) INs, are sufficient to desynchronize the network and shift the distribution of population variance. Through targeted ablation of a fraction of PV INs, we show dimensionality is highly correlated with stimulus decoding accuracy. Furthermore, PV INs undergo a sharp increase in transcriptional maturation between postnatal day (P) 8 and 11, during which they preferentially enrich for synaptic genes. Lastly, a novel, biologically plausible, multi-cell-type computational model reproduced the developmental desynchronization and rise in dimensionality. Strikingly, without being constrained by perturbation data, the model accurately predicted the effects of each IN class on the network that we observed empirically.

neuroscience↗

bioRxiv2026

Mesaconic acid delivery via biomaterials and engineered probiotics to the gut reduces inflammation in Crohn's Diseases mouse models

Mesaconate (MES, an immunosuppressive metabolite) but not itaconate is upregulated in stool of Crohns Disease (CD) patients, albeit below therapeutic levels.. However, colonic MES level is difficult to maintain because of its high absorption rate, limiting its therapeutic potential for CD. Herein, we developed two strategies that elevate MES level and suppress inflammation: EcN-CAD, an engineered probiotic Escherichia coli Nissle 1917 (EcN) that overexpresses cis-aconitate decarboxylase (CAD, produces itaconic acid that is converted to MES); and MES+Zn, a Zinc-MES ionically crosslinked formulation. Mechanistically, MES modulates T cell function by downregulating glycolytic and mitochondrial activity and decrease ROR{gamma}t expression. In preclinical SAMP1/YitFC dexamethasone-withdrawal model and TNFDARE model, MES+Zn decreased gut permeability significantly compared to controls and reduced myeloperoxidase (MPO, an inflammatory marker) 1000-fold compared to controls. EcN-CAD probiotics decreased ROR{gamma}t expression in CD4+ and CD8+ T cells, gut permeability and inflammation in preventive SAMP1/YitFC model, and SAMP1/YitFC dexamethasone-withdrawal model. Overall, MES rewires T cell responses and technologies that enhance MES levels can be effective in gut-related inflammatory diseases.

immunology↗

bioRxiv2026

Quantitative Systems Pharmacology Model for Trop-2 Targeting Antibody-Drug Conjugate in Triple-Negative Breast Cancer

TROP2-targeted antibody-drug conjugates (ADCs) have demonstrated promising clinical activity in triple-negative breast cancer (TNBC) as monotherapies; however, therapeutic benefit varies among patients. Combination strategies pairing TROP2-targeted ADCs with immune checkpoint inhibitors are also being investigated. Elucidating the mechanistic drivers of ADC monotherapy variability and enabling the rational development of combination regimens require computational frameworks that integrate ADC pharmacology with tumor-immune interactions. A quantitative systems pharmacology (QSP) model is presented that incorporates an ADC module into our established immuno-oncology model for TNBC. The module captures ADC and payload pharmacokinetics and pharmacodynamics. TNBC heterogeneity is represented by two tumor cell clones with high and low TROP2 expression, informed by prior characterizations, and differential sensitivity to the ADC payload is incorporated as an intrinsic property of each clone. Although generalizable, the model was applied to the TROP2-targeted ADC sacituzumab govitecan (SG, TRODELVY). A virtual patient cohort was generated using Latin hypercube sampling and calibrated against objective response rate (ORR) data from SG Phase I/II TNBC basket trial. The model predicted an ORR of 33.2% consistent with ASCENT study (NCT02574455). Simulations suggest TROP2-mediated delivery contributes modestly to SG efficacy with tumor exposure driven largely by systemically released SN-38 payload being sufficient to induce cytotoxicity. Tumor heterogeneity emerged as a key determinant of response with ORR increasing as the fraction of payload-sensitive clones increased. Overall, this QSP framework for TROP2-targeted ADCs accounts for TNBC heterogeneity and is extendable to other ADCs and targets enabling interrogation of ADC mechanisms of action in conjunction with tumor-immune interactions.

pharmacology and toxicology↗

bioRxiv2026

Cortical circuit implementation of signed deviant detection with positive and negative prediction error neurons

Predicting future events is fundamental for animals to adaptively interact with their environment, but whether and how the cerebral cortex processes predictive information remains an unresolved question. We combined in vivo two-photon calcium imaging in mouse somatosensory cortex with an oddball paradigm that decouples sensory stimulus properties from predictability context. We recorded neuronal responses in layer (L)2/3, bottom-up sensory inputs, and top-down prefrontal feedback. We find that L2/3 pyramidal neurons concurrently encode stimulus features and statistical context. We identify coexisting positive prediction error (PE) neurons that subtract predictions from incoming sensory inputs and negative PE neurons that do the opposite. This architecture represents a unified computational principle where error signals scale proportionally with the magnitude of mismatch across distinct stimulus features tested (amplitude, direction, omission). Furthermore, bottom-up pathways operate as unsigned novelty detectors, L2/3 circuit computes signed PE, and top-down projections signal a precision-weighted signed error, demonstrating hierarchical predictive processing.

neuroscience↗

bioRxiv2025

A comprehensive AMR genotype-phenotype database (CABBAGE)

Addressing the growing threat of antimicrobial resistance (AMR) requires the development of large-scale resources that link bacterial genomic data with phenotypic antimicrobial resistance profiles. Such datasets are essential for advancing genotype-based predictions of resistance to uncover novel resistance mechanisms, as well as identifying and tracking global trends. Here, we describe the development of the Comprehensive Assessment of Bacterial-Based AMR prediction from GEnotypes (CABBAGE) database, linking bacterial genomes to associated antibiotic susceptibility data and relevant metadata across WHO Bacterial Priority Pathogens, sourced from both publications and existing databases, and curated into a format that is compatible with, and extends, both NCBI and ENA formats. The resulting CABBAGE database, comprising over 170,000 unique sequenced isolates and approximately 1.7 million genome-phenotype pairs linked to extensive metadata, represents the largest database of its kind, consolidating existing AMR phenotype-genotype data into a single unified format. CABBAGE encompasses a broad range of antimicrobials, facilitating the analysis of global resistance trends as well as benchmarks of genotype-to-phenotype predictive methods, and empowering further research uses. The database is freely accessible at https://www.ebi.ac.uk/amr and is currently being integrated with the BioSample database, enabling easy access for the AMR research community.

genomics↗

bioRxiv2025

Epigenetic Reprogramming of Host Chromatin by the Transforming Parasite Theileria annulata

Theileria annulata, a transforming apicomplexan parasite, extensively reprograms the chromatin architecture of bovine leukocytes to facilitate infection and cellular transformation. To elucidate the underlying epigenetic mechanisms, we characterized the chromatin landscape of infected lymphocytes using integrated proteomic, imaging, and functional assays. Our findings reveal that T. annulata lacks the DNA damage marker {gamma}H2A.X and its associated SQ/TQ motif, indicating an evolutionary divergence from canonical DNA repair signalling pathways. High-resolution profiling of histone post-translational modifications (PTMs) demonstrated distinct nuclear compartmentalization, with host (H3K27me3, H3K9me1/2), parasite-predominant modifications (H3K4me3, H3K18me1, H3K27ac, H3K9ac, and H3K36me3), and shared modifications (e.g., H3K4me1/2, H3K36me2, H4K5/8/12/16ac, H3K9me3 and H4K91Ac) suggesting a coordinated epigenetic strategy driving host cell programs to sustain proliferation and survival. Our study delineates a novel host-parasite epigenetic interface, positioning T. annulata as a unique model of epigenetic parasitism. By bridging parasitology and cancer epigenetics, these findings unveil new therapeutic opportunities targeting chromatin vulnerabilities in parasite-induced transformation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/684985v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1bd0e05org.highwire.dtl.DTLVardef@e37ea4org.highwire.dtl.DTLVardef@18f78d5org.highwire.dtl.DTLVardef@460eb4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Proteomic Insights into Strong and Weak Biofilm Formation in Acinetobacter baumannii for Potential Therapeutic Targets

Acinetobacter baumannii is notable for its biofilm-forming abilities, which aid in its tolerance to antibiotics, adding to antimicrobial resistance. The clinical isolates present varied biofilm-forming capacity; hence, understanding the molecular determinants that result in strong biofilm development is crucial for drug target identification. This study is the first of its kind to compare proteome profiling of strong and weak biofilm-forming A. baumannii clinical isolates. Comparative proteomic profiling revealed 42 differentially regulated proteins. It was observed that in strong biofilm forming isolate NlpA, uL16, DNA gyrase B, acetyl-CoA carboxylase, and purl etc. were upregulated highlighting a dynamic reprogramming of cellular functions that promotes biofilm formation, stress adaptation, and immune evasion. In contrast, EF-Tu, ribosome hibernation factors, and T6SS components were downregulated, suggesting a lack of biosynthesis and stress adaptability. These findings suggest a metabolic downshift and a possible energy conservation mechanism under conditions less favorable for strong biofilm development. Additionally, several uncharacterized proteins were identified, highlighting potential novel factors in biofilm regulation and virulence that warrant further investigation. The proteomics data correlated with qPCR findings, providing support for the unknown regulators of biofilm formation that were identified in this study. Key proteins such as nlpA, 6,7-dimethyl-8-ribityllumazine synthase and DNA gyrase B emerged as potential therapeutic targets. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/680171v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1c9b95aorg.highwire.dtl.DTLVardef@a7e781org.highwire.dtl.DTLVardef@14fe64aorg.highwire.dtl.DTLVardef@9804f2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

microbiology↗

bioRxiv2025

A spatial atlas of chemoradiation therapy in pancreatic cancer identifies cellular and microenvironmental determinants of persister populations

The molecular pathways involved in the response to radiation therapy in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. We aimed to elucidate the adaptive mechanisms and cellular interactions within PDAC to radiation therapy (RT). We constructed a transcriptomic landscape of the cellular subtypes and spatially resolved neighborhoods from 50 patient samples, including 16 longitudinally matched single cell RNA sequencing and 34 spatial transcriptomics specimens. To resolve shortcomings of cell-type mixtures in spatial data, we developed a novel statistical method called SpaCCI (spatially aware analysis of cell-cell interactions) to profile cell-cell interactions and ligand-receptor enrichment. This revealed CXCL12/TGF{beta}-driven persister cell niches where activated fibroblasts reprogram tumor- associated macrophages and spatially exclude stress-response CD8 T cells after RT. Persister cancer cells displayed transcriptional evidence of recalcitrance to metal-induced cell death pathways of ferroptosis and cuproptosis which were recapitulated in preclinical models. Our study reveals the selective pressures experienced by PDAC following RT that may help provide insight for future multimodal therapeutic strategies.

cancer biology↗

bioRxiv2025

Facilitating User Interaction with the Tuberculosis Mutation Catalogue using AI Tools

The World Health Organization (WHO) 2023 Mutation Catalogue for Mycobacterium tuberculosis is a crucial knowledgebase and tool for clinical interpretation of mutations associated with drug-resistant TB. However, the documents complexity and size pose challenges for many users. This study evaluated the potential of generative artificial intelligence (AI) models to facilitate natural language user interaction with the catalogue. Four prominent AI models--Google Gemini 2.5 Pro, OpenAI ChatGPT 4.1, Perplexity AI, and DeepSeek R1--were assessed through general test questions, mutation search and retrieval tasks using both full catalogue queries and antibiotic-specific tables, and the application of additional grading rules to score novel mutations. Performance was measured based on accuracy, completeness, clarity, source citation, and the presence of hallucinations. Google Gemini 2.5 Pro consistently demonstrated superior performance in accuracy, completeness, and avoidance of hallucinations across most evaluations, especially in general queries and large dataset searches. DeepSeek R1 excelled in applying grading rules to novel mutations and showed high accuracy in focused datasets, but exhibited some hallucinations. ChatGPT 4.1 was strong in clarity but lacked proper citations, and Perplexity AI showed variable performance with a higher frequency of hallucinations. The findings highlight the potential of AI tools to enhance accessibility and utility of complex knowledgebases like the WHO Mutation Catalogue, while emphasizing the critical need for careful model selection and rigorous benchmarking to ensure accuracy and reliability. The results suggest that Google Gemini 2.5 Pro and DeepSeek R1 are strong candidates for developing a custom clinical AI agent to assist all levels of healthcare users in navigating and interpreting the complex information within the catalogue, ultimately contributing to improved TB control efforts.

bioinformatics↗

bioRxiv2025

Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of Fragile X mice and identifies EPAC2 as a therapeutic target.

Symptoms of Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell type specific mRNA sequencing to profile molecular alterations of cortical excitatory and inhibitory neurons in Fmr1 knockout (KO) mice, integrating transcriptomic results with circuit and behavioral readouts to prioritize novel therapeutic targets. Differentially expressed genes (DEG) were largely upregulated in Camk2a expressing excitatory neurons but downregulated in Pvalb-expressing inhibitory neurons, and the underlying signaling pathways were often altered in opposite directions. Among the 184 DEGs that were concordantly dysregulated across both cell types, only Rapgef4 (Epac2) was also an FMRP target, an ASD risk gene and brain enriched. EPAC2 has been implicated in synaptic maturation and plasticity. Systemic administration of an EPAC2 antagonist restored cortical circuit function in Fmr1 KO mice and ameliorated sensory behavioral phenotypes. EPAC2 is a potential target for therapy in FXS.

neuroscience↗

bioRxiv2025

A rapid non-traditional approach for developing biologicals against drug- resistant bacteria and yeasts.

Development of effective, long-lasting antibiotics is a challenge due to the rate at which the pathogens acquire resistance, prompting the major pharma players to omit them from their portfolio. We present a non-traditional approach for rapidly developing anti-infective biologicals that is resilient to resistance. Antibody-drug conjugates were developed against three different pathogens Pseudomonas aeruginosa (ABG 14), Staphylococcus aureus (ABG 16) and Candida. albicans (ABG 07) that were extremely specific and effective in neutralising them irrespective of their drug resistance profiles. Neutralising camelid antibody fragment (VHH) were isolated from immunised camel libraries by phage display that effectively neutralised the pathogens at a MIC 99 of 125 {micro}g mL-1 in vitro. Antimicrobial peptides (AMP) were then conjugated to them by pathogen-specific cleavable linkers and the resultant molecules were 10 -20 times more effective due to a dual mode of action-the inhibitory action of the VHH on surface transporters and enzymes and the activity of the AMPs released by the pathogen surface proteases. Called AbTids, these molecules were extremely specific, stable in plasma and were activated in the presence of 104 to 105 CFU mL-1 of the pathogens and had an efficacy in the sub-micromolar range (6.25-12.5 {micro}g mL-1, 250 nM) inhibiting their growth within 2 hrs. of administration. They were economically and efficiently produced in microbial production system as a single chain fusion protein. One of the molecules ABG 14 was characterised further and found to be pathogen specific with negligible frequency of resistance, was non-toxic, had the capability to destroy biofilms, and cleared a systemic infection in a mouse with a carbapenem resistant strain of P. aeruginosa at a dose of 5 mg kg-1. This strategy can be used to generate new hits against medically important pathogens in a matter of weeks by simply shuffling the components, using different VHHs and AMPs, bypassing years of expensive drug development efforts that can potentially rejuvenate drug discovery efforts against emerging superbugs.

microbiology↗

bioRxiv2024

LPS-induced sepsis disrupts brain activity in a region- and vigilance-state specific manner

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis and the systemic inflammatory response syndrome that leads to lasting consequences in survivors. It manifests as early EEG changes, that are region-, time- and state-specific, possibly reflecting distinct mechanisms of injury. Here, we investigated the effects of 5mg/kg lipopolysaccharide (LPS) on hippocampal and cortical sleep-wake states, oscillatory and non-oscillatory neuronal activity, as well as on within and between state dynamics using state-space analysis. LPS induced rapid-onset severe temporal and spatial vigilance state fragmentation, which preceded all other spectral changes by [~]90 minutes. Thereafter, LPS led to specific destabilization and increased delta oscillatory activity in wakefulness, but not NREM sleep, although state transitions remained largely normal. Instead, reduced NREM delta power resulted from aperiodic spectrum changes. LPS specifically reduced higher frequency hippocampal gamma oscillations (60-80Hz peak) in wakefulness, but not cortical high gamma or lower frequency gamma oscillations. These results suggest that disruption of sleep-wake patterns could serve as an early indicator of sepsis and associated encephalopathy, independent of spectral changes. Moreover, treatment aimed at stabilizing vigilance states in early stages of sepsis might prove to be a novel option preventing the development of further pathological neurophysiology, as well as limiting inflammation-related brain damage.

neuroscience↗

bioRxiv2024

Sterile kidney tissue injury induces neutrophil swarming in lung alveolar capillaries

Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with hypoxemia that does not improve with dialysis and remains incompletely understood. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induces rapid intravascular neutrophil retention in lung alveolar capillaries without any significant extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of any significant lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote lung inflammation did not require cues from intravascular non-classical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on neutrophil chemoattractant CXCL2 released by activated intravascular classical monocytes. Comparative single-cell RNA-sequencing analysis of direct and remote lung inflammation revealed that alveolar macrophages are highly activated and produce the neutrophil chemoattractant CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal administration of CXCL2 during AKI-induced remote lung inflammation enabled neutrophils to extravasate. We thus discovered important differences in lung neutrophil recruitment in direct versus remote lung inflammation and identified lung capillary neutrophil retention that negatively affects oxygenation by causing a ventilation-perfusion mismatch as a novel driver of AKI-induced hypoxemia.

physiology↗

bioRxiv2023

Exponentially decreasing exposure of antigen generates anti-inflammatory T-cell responses

Rheumatoid Arthritis (RA) is a chronic debilitating disease characterized by auto-immune reaction towards self-antigen such as collagen type II. In this study, we investigated the impact of exponentially decreasing levels of antigen exposure on pro-inflammatory T cell responses in the collagen-induced arthritis (CIA) mouse model. Using a controlled delivery experimental approach, we manipulated the collagen type II (CII) antigen concentration presented to the immune system. We observed that exponentially decreasing levels of antigen generated reduced pro-inflammatory T cell responses in secondary lymphoid organs in mice suffering from RA. Specifically, untreated mice exhibited robust pro-inflammatory T cell activation and increased paw inflammation, whereas, mice exposed to exponentially decreasing concentrations of CII demonstrated significantly reduced pro-inflammatory T cell responses, exhibited lower levels of paw inflammation, and decreased arthritis scores in right rear paw. The data also demonstrate that the decreasing antigen levels promoted the induction of regulatory T cells (Tregs), which play a crucial role in maintaining immune tolerance and suppressing excessive inflammatory responses. Our findings highlight the importance of antigen concentration in modulating pro-inflammatory T cell responses in the CIA model. These results provide valuable insights into the potential therapeutic strategies that target antigen presentation to regulate immune responses and mitigate inflammation in rheumatoid arthritis and other autoimmune diseases. Further investigations are warranted to elucidate the specific mechanisms underlying the antigen concentration-dependent modulation of T cell responses and to explore the translational potential of this approach for the development of novel therapeutic interventions in autoimmune disorders.

immunology↗

bioRxiv2023

Conformationally Adaptive Dyes Enable Protein-Adaptive Differential Scanning Fluorometry

Flexible in vitro methods alter the course of biological discoveries. Differential Scanning Fluorimetry (DSF) is a particularly versatile technique which reports protein thermal unfolding via fluorogenic dye. However, applications of DSF are limited by widespread protein incompatibilities with the available DSF dyes. Here, we enable DSF applications for 66 of 70 tested proteins (94%) including 10 from the SARS-CoV2 virus using a chemically diverse dye library, Aurora, to identify compatible dye-protein pairs in high throughput. We find that this protein-adaptive DSF platform (paDSF) not only triples the previous protein compatibility, but also fundamentally extends the processes observable by DSF, including interdomain allostery in O-GlcNAc Transferase (OGT). paDSF enables routine measurement of protein stability, dynamics, and ligand binding. One-Sentence SummaryNext generation protein-adaptive DSF (paDSF) enables rapid and general measurements of protein stability and dynamics.

biochemistry↗

bioRxiv2023

Establishment and Characterization of Three Novel CAF Cell Lines from HNSCC Patients

Due to the high rates of tobacco chewers, smokers, and alcohol consumers in India, Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the primary causes of mortality. Being profoundly varied in nature, treating patients diagnosed with HNSCC can be difficult. An in vitro cell line model is needed to better comprehend the heterogeneity especially via the interaction with components of the microenvironment like Cancer Associated Fibroblasts (CAFs). The effectiveness of creating cell lines from head and neck cancers is, however, poor. Furthermore, except for the two reported earlier by us, no other CAF cell lines are available to study the cross-talk of the tumor with its microenvironment. In this study, we report three novel CAF lines, spontaneously immortalized from HPV negative male patients with habits of tobacco and diagnosed with squamous cell carcinoma of the upper alveolus, larynx and buccal mucosa as opposed to HPV positive non-habitual female patients with cancer of the tongue as previously reported. The CAFs increased the tumorigenicity of epithelial cells in indirect co-culture experiments. Negative staining with EpCAM, CD31 and CD45, while positive staining with FSP-1 determined their fibroblast specific lineage. The developed CAF cultures are the first of their kind from the mentioned sites, and they will be an invaluable tool for learning how tumor-stroma and tumor interact with one another and discovering newer targets and pathways for treating HNSCC.

cancer biology↗

bioRxiv2022

Improvement of sensory deficits in Fragile X mice by increasing cortical interneuron activity after the critical period

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches in postnatal mouse somatosensory cortex (S1), we find that parvalbumin (PV) IN precursors are hypoactive and decoupled from excitatory neurons in Fmr1-/- mice, a model of Fragile X Syndrome (FXS). This leads to a loss of PV-INs in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1-/- mice restores PV density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering a novel allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

neuroscience↗

bioRxiv2022

MYC Overexpression Drives Immune Evasion in Human Cancer that is Reversible Through Restoration of Pro-Inflammatory Macrophages

Cancers evade immune surveillance that in some, but not in many, cases can be reversed through immune checkpoint therapy. Here we report that the MYC oncogene suppresses immune surveillance, activates immune checkpoint expression, and predicts responsiveness to immune checkpoint inhibition. First, when MYC is genomically amplified and overexpressed in 33 different human cancers, this increases immune checkpoint expression, drives immune checkpoint therapeutic resistance, and is associated with both Th2-like immune profile, and reduced CD8 T cell infiltration. Second, experimentally, MYC-driven tumors suppress pro-inflammatory antigen-presenting macrophages with increased CD40 and MHCII expression, which in turn impedes T cell response. This MYC-driven suppression of macrophages can be reversed by combined but not individual blockade of PDL1 and CTLA4. Third, the depletion of macrophages abrogated the anti-neoplastic effects of PDL1 and CTLA4 blockade. Hence, MYC is a predictor of immune checkpoint responsiveness and a key driver of immune evasion through the suppression of pro-inflammatory macrophages. The immune evasion by MYC can be overcome by combined PDL1 and CTLA4 blockade. Statement of SignificanceMYC is the most commonly activated oncogene in human cancers. In this study, we identify macrophage-mediated immune evasion as a major therapeutic vulnerability of MYC-driven cancers. Our results have implications for developing effective immunotherapies for MYC-driven human cancers and also for prioritizing patients with MYC-driven tumors for combination immunotherapy.

cancer biology↗