Brianna Dalesandro

Anal Chem. 2022 May 17;94(19):6957-6966. doi: 10.1021/acs.analchem.1c05006. Epub 2022 May 2.

ABSTRACT

The rapid identification and antibiotic susceptibility testing (AST) of bacteria would help us to accurately identify the infectious sources as well as guide the use of antibiotics, which are crucial for improving the survival rate and antimicrobial resistance. Herein, a colorimetric sensor array for bacteria fingerprinting was constructed with d-amino acid (d-AA)-modified gold nanoparticles (AuNPs) as probes (Au/d-AA). Bacteria can metabolize the d-AA, triggering the aggregation of AuNPs. Making use of different metabolic capabilities of bacteria toward different d-AA, eight kinds of bacteria including antibiotic-resistant bacteria and strains of the same bacterial species are successfully differentiated via learning the response patterns. Meanwhile, the sensor array also performs well in quantitative analysis of single bacterium and differentiation of bacteria mixtures. More interestingly, a rapid colorimetric AST approach has been developed based on the Au/d-AA nanoprobes by monitoring the d-AA metabolic activity of bacteria toward various antibiotic treatments. In this regard, the outlined work here would promote clinical practicability and facilitate antibiotic stewardship.

PMID:35500293 | DOI:10.1021/acs.analchem.1c05006

Nano Lett. 2022 Jun 22;22(12):5055-5064. doi: 10.1021/acs.nanolett.2c00699. Epub 2022 May 18.

ABSTRACT

Oncolytic viruses (OVs) have been widely used as anticancer therapeutics because of their systemic immune responses during viral replication. However, the low enrichment of OVs within tumors and limited immune activation have hindered their clinical application. Herein, we proposed the concept of bacteria-assisted targeting of OVs to tumors, with liposome-cloaked oncolytic adenoviruses (OAs) conjugated onto tumor-homing Escherichia coli BL21 (designated as E. coli-lipo-OAs) for enhanced cancer immunotherapy. Notably, the enrichment of OAs transported by self-propelled bacterial microbe vehicles in E. coli-lipo-OAs in a nonsmall cell lung tumor can be potentiated by more than 170-fold compared with that of intravenously injected bare OAs. In vivo studies further revealed that E. coli-lipo-OAs administered intravenously significantly enhanced antitumor immunity through bacterial-viral-augmented immune responses. Our findings suggest that the self-driving microbe vehicle as a systemic delivery system for OVs can be a potent platform for developing future anticancer biotherapeutics at the clinical level.

PMID:35583490 | DOI:10.1021/acs.nanolett.2c00699

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R5594.

ABSTRACT

The antibiotic vancomycin is used as a last resort to treat persistent infections caused by Gram-positive pathogens. Vancomycin kills bacteria by binding a peptidoglycan precursor, thereby inhibiting cell-wall biosynthesis. An alarming type of resistance to this antibiotic comes in the form of vancomycin-resistant Enterococci(VRE). VRE have acquired genes that allow them to remodel the cell-wall precursor and prevent vancomycin binding. Expression of these remodeling genes is under control of the VanSR two-component system. VanS is a membrane-bound sensor kinase that recognizes the vancomycin signal, and in response activates the transcription factor VanR, which activates expression of the remodeling genes. However, very little is known about how VanS senses the antibiotic. To date, nine different types of VRE have been discovered, with VanA and VanB types responsible for the vast majority of human infections. Since vancomycin can induce the expression of both VanA and VanB resistance genes, we hypothesize that the VanS proteins from these types are activated by directly binding to vancomycin. We used in vitro autokinase assays to show that vancomycin directly activates VanS from VanB VRE (VanS_B ), while having no direct effect on VanS_A- . We isolated the VanS_B periplasmic sensor domain and used fluorescence anisotropy to show that it directly binds to a fluorescent vancomycin analog. Computational modeling predicts that the VanS_B sensor domain adopts a PAS-like fold, and HDX-MS experiments supported this prediction and identified a potential vancomycin-binding site. We also developed vancomycin photoprobes to confirm this binding site and to elucidate vancomycin's orientation in the interaction. These results demonstrate how VanS_B can directly sense vancomycin in the environment to activate the resistance mechanism in VanB VRE, providing a promising therapeutic target to combat these dangerous pathogens.

PMID:35555785 | DOI:10.1096/fasebj.2022.36.S1.R5594

ACS Synth Biol. 2022 May 13. doi: 10.1021/acssynbio.1c00397. Online ahead of print.

ABSTRACT

Receptor downregulation is instrumental for many therapeutic interventions. Receptor knockout through gene-editing technologies is efficient but can introduce off-target mutations and chromothripsis. Regulation of gene expression at the protein level is a promising alternative. Here, we present results showing the targeted T cell antigen receptor (TCR) degradation using chimeric E3 fusion proteins that we call Receptor Targeting Chimeras (ReceptorTAC). We show that TCR degradation is dependent on enzymatically active, membrane-anchored E3 ligase variants. TCR specificity was achieved by direct fusion of an E3 domain to the CD3ζ transmembrane sequence. Jurkat and primary T cells stably expressing the ReceptorTAC constructs showed significantly reduced responses to TCR stimulation. We also used our ReceptorTAC technology to generate TCR-deficient, claudin18.2-specific CAR T cells, where the activity of the CAR was unaffected by the expression of the ReceptorTAC. These data indicate that our ReceptorTAC molecule can be used to generate allogeneic CAR T cells.

PMID:35549091 | DOI:10.1021/acssynbio.1c00397

Nat Commun. 2022 May 11;13(1):2576. doi: 10.1038/s41467-022-30216-8.

ABSTRACT

Engineered natural killer (NK) cells represent a promising option for immune therapy option due to their immediate availability in allogeneic settings. Severe acute diseases, such as COVID-19, require targeted and immediate intervention. Here we show engineering of NK cells to express (1) soluble interleukin-15 (sIL15) for enhancing their survival and (2) a chimeric antigen receptor (CAR) consisting of an extracellular domain of ACE2, targeting the spike protein of SARS-CoV-2. These CAR NK cells (mACE2-CAR_sIL15 NK cells) bind to VSV-SARS-CoV-2 chimeric viral particles as well as the recombinant SARS-CoV-2 spike protein subunit S1 leading to enhanced NK cell production of TNF-α and IFN-γ and increased in vitro and in vivo cytotoxicity against cells expressing the spike protein. Administration of mACE2-CAR_sIL15 NK cells maintains body weight, reduces viral load, and prolongs survival of transgenic mice expressing human ACE2 upon infection with live SARS-CoV-2. These experiments, and the capacity of mACE2-CAR_sIL15 NK cells to retain their activity following cryopreservation, demonstrate their potential as an allogeneic off-the-shelf therapy for COVID-19 patients who are faced with limited treatment options.

PMID:35546150 | PMC:PMC9095674 | DOI:10.1038/s41467-022-30216-8

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.0R324.

ABSTRACT

Antibiotic resistance has been a reality ever since the discovery of penicillin, yet with the overuse and misuse of antibiotics since the 1940s, antibiotic resistant infections are on the rise. Compounding the problem, over the past few decades antibiotic discovery and development has slowed. As a result, we are facing a crisis that is expected to create up to 10 million deaths globally by 2050 without urgent action. Selective pressure from antibiotics allows bacteria to generate a variety of resistance mechanisms, creating infections that can become severe and difficult or impossible to treat. Even many antibiotics deemed "last resort" are diminishing in effectiveness due to the emergence of highly resistant bacteria. Among these "last resort" antibiotics are glycopeptides that target bacterial cell wall synthesis in Gram-positive bacteria. Specifically, a precursor molecule to peptidoglycan synthesis, known as lipid II, is a common target for glycopeptides. To evade these antibiotics, the structure of lipid II is often modified to prevent glycopeptide binding. As bacterial resistance to the glycopeptides spreads, new antibiotics must be made to combat these differences in lipid II molecules. Most approaches to increasing the availability of new antibiotics fall into two categories-reducing time required for discovery and reducing cost of development. This research outlines a novel strategy for antibiotic design using directed evolution techniques. By taking advantage of selective processes, much like those that drive resistance, directed evolution can be used to develop novel antibiotics that meet both these needs. In addition to keeping up with the pace of antibiotic resistance, directed evolution also offers the opportunity to drive more personalized medicine in healthcare. Streamlining the discovery process may ultimately make it possible to take bacterial samples from patients and rapidly create antibiotics specific to their infections. Single domain antibodies, or nanobodies, are a class of molecules with favorable properties for use as antibiotics given their size, stability, and potential antigen specificity. This poster focuses on the directed evolution of nanobodies for use as antibacterial molecules against lipid II in Gram-positive bacteria. In addition, it outlines a unique antigen selection strategy that is expected to be broadly applicable to a wide range of Gram-positive pathogens.

PMID:35555791 | DOI:10.1096/fasebj.2022.36.S1.0R324

Int Immunopharmacol. 2022 May 10;109:108783. doi: 10.1016/j.intimp.2022.108783. Online ahead of print.

ABSTRACT

The rapid development of bioengineering technology has introduced Fc-fusion proteins, representing a novel kind of recombinant protein, as promising biopharmaceutical products in tumor therapy. Numerous related anti-tumor Fc-fusion proteins have been investigated and are in different stages of development. Fc-fusion proteins are constructed by fusing the Fc-region of the antibody with functional proteins or peptides. They retain the bioactivity of the latter and partial properties of the former. This structural and functional advantage makes Fc-fusion proteins an effective tool in tumor immunotherapy, especially for the recruitment and activation of natural killer (NK) cells, which play a critical role in tumor immunotherapy. Even though tumor cells have developed mechanisms to circumvent the cytotoxic effect of NK cells or induce defective NK cells, Fc-fusion proteins have been proven to effectively activate NK cells to kill tumor cells in different ways, such as antibody-dependent cell-mediated cytotoxicity (ADCC), activate NK cells in different ways in order to promote killing of tumor cells. In this review, we focus on NK cell-based immunity for cancers and current research progress of the Fc-fusion proteins for anti-tumor therapy by activating NK cells.

PMID:35561479 | DOI:10.1016/j.intimp.2022.108783

Sci Rep. 2022 May 10;12(1):7677. doi: 10.1038/s41598-022-11648-0.

ABSTRACT

Antibody-Drug Conjugates (ADCs) have rapidly expanded in the clinic, with 7 new approvals in 3 years. For solid tumors, high doses of ADCs improve tissue penetration and efficacy. These doses are enabled by lower drug-to-antibody ratios and/or co-administration of unconjugated antibody carrier doses to avoid payload toxicity. While effective for highly expressed targets, these strategies may not maintain efficacy with lower target expression. To address this issue, a carrier dose that adjusts binding in situ according to cellular expression was designed using computational modeling. Previous studies demonstrated that coadministration of unconjugated antibody with the corresponding ADC at an 8:1 ratio improves ADCs efficacy in high HER2 expressing tumors. By designing a High Avidity, Low Affinity (HALA) carrier antibody, ADC binding is partially blocked in high expression cells, improving tissue penetration. In contrast, the HALA antibody cannot compete with the ADC in low expressing cells, allowing ADC binding to the majority of receptors. Thus, the amount of competition from the carrier dose automatically adjusts to expression levels, allowing tailored competition between different patients/metastases. The computational model highlights two dimensionless numbers, the Thiele modulus and a newly defined competition number, to design an optimal HALA antibody carrier dose for any target.

PMID:35538109 | PMC:PMC9090802 | DOI:10.1038/s41598-022-11648-0

Microbiol Spectr. 2022 May 10:e0168821. doi: 10.1128/spectrum.01688-21. Online ahead of print.

ABSTRACT

The human microbiome project has revolutionized our understanding of the interaction between commensal microbes and human health. By far, the biggest perturbation of the microbiome involves use of broad-spectrum antibiotics excreted in the gut. Thus, pharmacodynamics of microbiome changes in relation to drug exposure pharmacokinetics is an emerging field. However, reproducibility studies are necessary to develop the field. A simple and fast high-performance liquid chromatography-photodiode array detector (HPLC) method was validated for quantitative fecal vancomycin analysis. Reproducibility of results were tested based on sample storage time, homogeneity of antibiotic within stool, and concentration consistency after lyophilization. The HPLC method enabled the complete elution of vancomycin within ~4.2 min on the reversed-phase C18 column under the isocratic elution mode, with excellent recovery (85% to 110%) over a 4-log, quantitative range (0.4-100 μg/mL). Relative standard derivations (RSD) of intra-day and inter-day results ranged from 0.4% to 5.4%. Using sample stool aliquots of various weights consistently demonstrated similar vancomycin concentrations (mean RSD: 6%; range: 2-16%). After correcting for water concentrations, vancomycin concentrations obtained after lyophilization were similar to the concentrations obtained from the original samples (RSD less than 10%). These methodologies establish sample condition standards for a quantitative HPLC to enable vancomycin pharmacokinetic studies with the human microbiome. IMPORTANCE Research on antibiotic effect on the gut microbiome is an emerging field with standardization of research methods needed. In this study, a simple and fast high-performance liquid chromatography method was validated for quantitative fecal vancomycin analysis. Reproducibility of results were tested to standardize storage time, homogeneity of antibiotic within stool, and concentration consistency after lyophilization. These methodologies establish sample condition standards for a quantitative HPLC to enable vancomycin pharmacokinetic studies with the human microbiome.

PMID:35536037 | DOI:10.1128/spectrum.01688-21

Adv Drug Deliv Rev. 2022 Jul;186:114321. doi: 10.1016/j.addr.2022.114321. Epub 2022 May 6.

ABSTRACT

Bacterial membrane vesicles (BMVs) have emerged as novel and promising platforms for the development of vaccines and immunotherapeutic strategies against infectious and noninfectious diseases. The rich microbe-associated molecular patterns (MAMPs) and nanoscale membrane vesicle structure of BMVs make them highly immunogenic. In addition, BMVs can be endowed with more functions via genetic and chemical modifications. This article reviews the immunological characteristics and effects of BMVs, techniques for BMV production and modification, and the applications of BMVs as vaccines or vaccine carriers. In summary, given their versatile characteristics and immunomodulatory properties, BMVs can be used for clinical vaccine or immunotherapy applications.

PMID:35533789 | DOI:10.1016/j.addr.2022.114321

Cell Chem Biol. 2022 May 19;29(5):741-756. doi: 10.1016/j.chembiol.2022.04.004. Epub 2022 May 4.

ABSTRACT

Intracellular bacteria have developed a multitude of mechanisms to influence the post-translational modifications (PTMs) of host proteins to pathogen advantages. The recent explosion of insights into the diversity and sophistication of host PTMs and their manipulation by infectious agents challenges us to formulate a comprehensive vision of this complex and dynamic facet of the host-pathogen interaction landscape. As new discoveries continue to shed light on the central roles of PTMs in infectious diseases, technological advances foster our capacity to detect old and new PTMs and investigate their control and impact during pathogenesis, opening new possibilities for chemical intervention and infection treatment. Here, we present a comprehensive overview of these pathogenic mechanisms and offer perspectives on how these insights may contribute to the development of a new class of therapeutics that are urgently needed to face rising antibiotic resistances.

PMID:35512694 | DOI:10.1016/j.chembiol.2022.04.004

Front Microbiol. 2022 Apr 18;13:822369. doi: 10.3389/fmicb.2022.822369. eCollection 2022.

ABSTRACT

Streptococcus suis (S. suis) is a common swine pathogen but also poses a threat to human health in causing meningitis and severe cases of streptococcal toxic shock-like syndrome (STSLS). Therefore, it is crucial to understand how S. suis interacts with the host immune system during bacteremia. As S. suis has the ability to introduce d-alanine into its lipoteichoic acids (LTAs), we investigated the working hypothesis that cell wall modification by LTA d-alanylation influences the interaction of S. suis with porcine blood immune cells. We created an isogenic mutant of S. suis strain 10 by in-frame deletion of the d-alanine d-alanyl carrier ligase (DltA). d-alanylation of LTAs was associated with reduced phagocytosis of S. suis by porcine granulocytes, reduced deposition of complement factor C3 on the bacterial surface, increased hydrophobicity of streptococci, and increased resistance to cationic antimicrobial peptides (CAMPs). At the same time, survival of S. suis was not significantly increased by LTA d-alanylation in whole blood of conventional piglets with specific IgG. However, we found a distinct cytokine pattern as IL-1β but not tumor necrosis factor (TNF)-α levels were significantly reduced in blood infected with the ΔdltA mutant. In contrast to TNF-α, activation and secretion of IL-1β are inflammasome-dependent, suggesting a possible influence of LTA d-alanylation on inflammasome regulation. Especially in the absence of specific antibodies, the association of S. suis with porcine monocytes was reduced by d-alanylation of its LTAs. This dltA-dependent phenotype was also observed with a non-encapsulated dltA double mutant indicating that it is independent of capsular polysaccharides. High antibody levels caused high levels of S. suis-monocyte-association followed by inflammatory cell death and strong production of both IL-1β and TNF-α, while the influence of LTA d-alanylation of the streptococci became less visible. In summary, the results of this study expand previous findings on d-alanylation of LTAs in S. suis and suggest that this pathogen specifically modulates association with blood leukocytes through this modification of its surface.

PMID:35509315 | PMC:PMC9058155 | DOI:10.3389/fmicb.2022.822369

ACS Cent Sci. 2022 Apr 27;8(4):430-440. doi: 10.1021/acscentsci.1c01570. Epub 2022 Mar 16.

ABSTRACT

The considerable utility of glycoside phosphorylases (GPs) has led to substantial efforts over the past two decades to expand the breadth of known GP activities. Driven largely by the increase of available genomic DNA sequence data, the gap between the number of sequences in the carbohydrate active enzyme database (CAZy DB) and its functionally characterized members continues to grow. This wealth of sequence data presented an exciting opportunity to explore the ever-expanding CAZy DB to discover new GPs with never-before-described functionalities. Utilizing an in silico sequence analysis of CAZy family GH94, we discovered and then functionally and structurally characterized the new GP β-1,3-N-acetylglucosaminide phosphorylase. This new GP was sourced from the genome of the cell-wall-less Mollicute bacterium, Acholeplasma laidlawii and was found to synthesize β-1,3-linked N-acetylglucosaminide linkages. The resulting poly-β-1,3-N-acetylglucosamine represents a new, previously undescribed biopolymer that completes the set of possible β-linked GlcNAc homopolysaccharides together with chitin (β-1,4) and PNAG (poly-β-1,6-N-acetylglucosamine). The new biopolymer was denoted acholetin, a combination of the genus Acholeplasma and the polysaccharide chitin, and the new GP was thus denoted acholetin phosphorylase (AchP). Use of the reverse phosphorolysis action of AchP provides an efficient method to enzymatically synthesize acholetin, which is a new biodegradable polymeric material.

PMID:35505869 | PMC:PMC9052796 | DOI:10.1021/acscentsci.1c01570

Chem Soc Rev. 2022 May 23;51(10):3886-3897. doi: 10.1039/d2cs00141a.

ABSTRACT

Degrader-antibody conjugates (DACs) are novel entities that combine a proteolysis targeting chimera (PROTAC) payload with a monoclonal antibody via some type of chemical linker. This review provides a current summary of the DAC field. Many general aspects associated with the creation and biological performance of traditional cytotoxic antibody-drug conjugates (ADCs) are initially presented. These characteristics are subsequently compared and contrasted with related parameters that impact DAC generation and biological activity. Several examples of DACs assembled from both the scientific and the patent literature are utilized to highlight differing strategies for DAC creation, and specific challenges associated with DAC construction are documented. Collectively, the assembled examples demonstrate that biologically-active DACs can be successfully prepared using a variety of PROTAC payloads which employ diverse E3 ligases to degrade multiple protein targets.

PMID:35506708 | DOI:10.1039/d2cs00141a

J Clin Invest. 2022 May 2;132(9):e152383. doi: 10.1172/JCI152383.

ABSTRACT

Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell-mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell-mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.

PMID:35499080 | PMC:PMC9057585 | DOI:10.1172/JCI152383

Cancer Discov. 2022 May 2;12(5):1336-1355. doi: 10.1158/2159-8290.CD-21-0929.

ABSTRACT

Microbes and their byproducts have been reported to regulate host health and immune functions. Here we demonstrated that microbial exopolysaccharide produced by Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 (EPS-R1) induced CCR6+ CD8+ T cells of mice and humans. In mice, ingestion of EPS-R1 augmented antitumor effects of anti-CTLA-4 or anti-PD-1 monoclonal antibody against CCL20-expressing tumors, in which infiltrating CCR6+ CD8+ T cells were increased and produced IFNγ accompanied by a substantial immune response gene expression signature maintaining T-cell functions. Of note, the antitumor adjuvant effect of EPS-R1 was also observed in germ-free mice. Furthermore, the induction of CCR6 expression was mediated through the phosphorylated structure in EPS-R1 and a lysophosphatidic acid receptor on CD8+ T cells. Overall, we find that dietary EPS-R1 consumption induces CCR6+ CD8+ T cells in Peyer's patches, favoring a tumor microenvironment that augments the therapeutic effect of immune-checkpoint blockade depending on CCL20 production by tumors.

SIGNIFICANCE: Gut microbiota- and probiotic-derived metabolites are attractive agents to augment the efficacy of immunotherapies. Here we demonstrated that dietary consumption of Lactobacillus-derived exopolysaccharide induced CCR6+ CD8+ T cells in Peyer's patches and improved the tumor microenvironment to augment the therapeutic effects of immune-checkpoint blockade against CCL20-producing tumors. See related commentary by Di Luccia and Colonna, p. 1189. This article is highlighted in the In This Issue feature, p. 1171.

PMID:35180303 | PMC:PMC9662940 | DOI:10.1158/2159-8290.CD-21-0929

Nat Commun. 2022 Apr 27;13(1):2278. doi: 10.1038/s41467-022-29836-x.

ABSTRACT

Maintenance of bacterial cell shape and resistance to osmotic stress by the peptidoglycan (PG) renders PG biosynthetic enzymes and precursors attractive targets for combating bacterial infections. Here, by applying native mass spectrometry, we elucidate the effects of lipid substrates on the PG membrane enzymes MraY, MurG, and MurJ. We show that dimerization of MraY is coupled with binding of the carrier lipid substrate undecaprenyl phosphate (C₅₅-P). Further, we demonstrate the use of native MS for biosynthetic reaction monitoring and find that the passage of substrates and products is controlled by the relative binding affinities of the different membrane enzymes. Overall, we provide a molecular view of how PG membrane enzymes convey lipid precursors through favourable binding events and highlight possible opportunities for intervention.

PMID:35477938 | PMC:PMC9046198 | DOI:10.1038/s41467-022-29836-x

Mol Ther. 2022 Apr 18:S1525-0016(22)00237-4. doi: 10.1016/j.ymthe.2022.04.008. Online ahead of print.

ABSTRACT

Tumor necrosis factor α (TNF-α) is upregulated in a chronic inflammatory environment, including tumors, and has been recognized as a pro-tumor factor in many cancers. Applying the traditional TNF-α antibodies that neutralize TNF-α activity, however, only exerts modest anti-tumor efficacy in clinical studies. Here, we develop an innovative approach to target TNF-α that is distinct from the neutralization mechanism. We employed phage display and yeast display to select non-neutralizing antibodies that can piggyback on TNF-α and co-internalize into cells through receptor ligation. When conjugating with toxins, the antibody exhibited cytotoxicity to cancer cells in a TNF-α-dependent manner. We further implemented the immunotoxin to an E. coli vehicle specially engineered for a high secretion level. In a syngeneic murine melanoma model, the bacteria stimulated TNF-α expression that synergized with the secreted immunotoxin and greatly inhibited tumor growth. The treatment also dramatically remodeled the tumor microenvironment in favor of several anti-tumor immune cells, including N1 neutrophils, M1 macrophages, and activated CD4⁺ and CD8⁺ lymphocytes. We anticipate that our new piggyback strategy is generalizable to targeting other soluble ligands and/or conjugates with different drugs for managing a diverse set of diseases.

PMID:35440418 | DOI:10.1016/j.ymthe.2022.04.008