Journal Articles

Cancer-associated SF3B1-K700E mutation controls immune responses by regulating T(reg) function via aberrant Anapc13 splicing

Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic malignancies, with SF3B1-K700E being the most common one. Here, we show that regulatory T cell (T(reg))-specific expression of SF3B1-K700E (Sf3b1(K700Efl/+)/Foxp3(YFP-Cre)) results in spontaneous autoimmune phenotypes. CD4(+) T cells from Sf3b1(K700Efl/+)/Foxp3(YFP-Cre) mice display defective T(reg) differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by Sf3b1(K700Efl/+)/Foxp3(YFP-Cre) T(regs). Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator Anapc13 due to the insertion of a 231-base pair DNA fragment to the 5' untranslated region. Forced expression of the Anapc13 gene restores the differentiation and ability of Sf3b1(K700Efl/+)/Foxp3(YFP-Cre) T(regs) to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, Sf3b1(K700Efl/+)/Foxp3(YFP-Cre) mice compared to Foxp3(YFP-Cre) mice. Our results highlight the impact of cancer-associated SF3B1 mutation on immune responses, which affect cancer development.

Author Info: (1) Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (2) Depar

Author Info: (1) Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (2) Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (3) Department of Botany & Plant Sciences, University of California, Riverside, CA 92527, USA. (4) Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (5) Department of System Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (6) Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (7) Translational Bioinformatics, Department of Computational Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (8) Integrated Genomics Core, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (9) Gehr Family Center for Leukemia Research, Department of Hematological Malignancies Translational Science, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (10) Department of System Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (11) Department of Botany & Plant Sciences, University of California, Riverside, CA 92527, USA. (12) Gehr Family Center for Leukemia Research, Department of Hematological Malignancies Translational Science, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. (13) Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.

Prediction of immunotherapy response using mutations to cancer protein assemblies

While immune checkpoint inhibitors have revolutionized cancer therapy, many patients exhibit poor outcomes. Here, we show immunotherapy responses in bladder and non-small cell lung cancers are effectively predicted by factoring tumor mutation burden (TMB) into burdens on specific protein assemblies. This approach identifies 13 protein assemblies for which the assembly-level mutation burden (AMB) predicts treatment outcomes, which can be combined to powerfully separate responders from nonresponders in multiple cohorts (e.g., 76% versus 37% bladder cancer 1-year survival). These results are corroborated by (i) engineered disruptions in the predictive assemblies, which modulate immunotherapy response in mice, and (ii) histochemistry showing that predicted responders have elevated inflammation. The 13 assemblies have diverse roles in DNA damage checkpoints, oxidative stress, or Janus kinase/signal transducers and activators of transcription signaling and include unexpected genes (e.g., PIK3CG and FOXP1) for which mutation affects treatment response. This study provides a roadmap for using tumor cell biology to factor mutational effects on immune response.

Author Info: (1) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (2) Department of Medicine and Moores Cancer Center

Author Info: (1) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (2) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (3) Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA. (4) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (5) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (6) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (8) Lunit Incorporated, Seoul, South Korea. (9) Lunit Incorporated, Seoul, South Korea. (10) Lunit Incorporated, Seoul, South Korea. (11) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (12) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA. Department of Bioengineering, University of California San Diego, San Diego, CA, USA.

Two-dose priming immunization amplifies humoral immunity by synchronizing vaccine delivery with the germinal center response

Prolonging exposure to subunit vaccines during the primary immune response enhances humoral immunity. Escalating-dose immunization (EDI), administering vaccines every other day in an increasing pattern over 2 weeks, is particularly effective but challenging to implement clinically. Here, using an HIV Env trimer/saponin adjuvant vaccine, we explored simplified EDI regimens and found that a two-shot regimen administering 20% of the vaccine followed by the remaining 80% of the dose 7 days later increased T(FH) responses 6-fold, antigen-specific germinal center (GC) B cells 10-fold, and serum antibody titers 10-fold compared with bolus immunization. Computational modeling of T(FH) priming and the GC response suggested that enhanced activation/antigen loading on dendritic cells and increased capture of antigen delivered in the second dose by follicular dendritic cells contribute to these effects, predictions we verified experimentally. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.

Author Info: (1) Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusett

Author Info: (1) Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. (2) Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. (3) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (4) Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. (5) Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (6) Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (7) Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (8) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. (9) Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (10) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (11) Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (12) Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Department of Physics, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. (13) Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Surgical outcomes following neoadjuvant chemotherapy with and without immunotherapy in patients with triple-negative breast cancer

PURPOSE: Adding pembrolizumab to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) improves pathologic complete response (pCR) rates and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes is unknown. This study compares 90-day post-surgical complications (PSCs) and time to adjuvant treatment among patients undergoing NAC for TNBC with and without immunotherapy. METHODS: Patients treated with NAC alone or with immunotherapy (NAC-I) for stage I-III TNBC between 2018 and 2022 were retrospectively identified at a single academic institution. Kruskal-Wallis rank sum and Fisher's exact tests compared patient sociodemographic and clinical characteristics. Multivariable logistic regression determined odds ratios (OR) predicting PSCs. RESULTS: Of 54 patients, 29 received NAC alone and 25 received NAC-I. Compared to NAC patients, NAC-I patients had more advanced stage tumors (p_=_0.038), and had slightly higher rates of mastectomy with reconstruction (p_=_0.193). 72.0% of NAC-I patients experienced a pCR, compared with 44.8% of NAC patients (p_=_0.193). There were 10 PSCs (34.5%) in NAC patients compared to 9 PSCs (36.0%) in NAC-I patients (p_>_0.99). Regression analysis demonstrated no association of PSCs with NAC-I (OR 0.83, 95% CI 0.19-3.60). Time to adjuvant therapy was shorter for NAC-I patients (28 days vs 36 days, p_=_0.013). CONCLUSIONS: Patients with TNBC receiving NAC-I have higher pCR rates and do not appear to have added 90-day PSCs or delays to adjuvant therapy despite trending toward more extensive surgical procedures compared to NAC alone. Larger studies are needed to further evaluate the surgical safety of immunotherapy.

Author Info: (1) Holy Cross and University of Miami, Fort Lauderdale, FL, USA. (2) Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, U

Author Info: (1) Holy Cross and University of Miami, Fort Lauderdale, FL, USA. (2) Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. (3) Division of Hematology and Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (4) Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. (5) Division of Hematology and Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (6) Division of Surgical Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. nskapoor@mednet.ucla.edu.

Fc-empowered exosomes with superior epithelial layer transmission and lung distribution ability for pulmonary vaccination

Mucosal vaccines offer potential benefits over parenteral vaccines for they can trigger both systemic immune protection and immune responses at the predominant sites of pathogen infection. However, the defense function of mucosal barrier remains a challenge for vaccines to overcome. Here, we show that surface modification of exosomes with the fragment crystallizable (Fc) part from IgG can deliver the receptor-binding domain (RBD) of SARS-CoV-2 to cross mucosal epithelial layer and permeate into peripheral lung through neonatal Fc receptor (FcRn) mediated transcytosis. The exosomes F-L-R-Exo are generated by genetically engineered dendritic cells, in which a fusion protein Fc-Lamp2b-RBD is expressed and anchored on the membrane. After intratracheally administration, F-L-R-Exo is able to induce a high level of RBD-specific IgG and IgA antibodies in the animals' lungs. Furthermore, potent Th1 immune-biased T cell responses were also observed in both systemic and mucosal immune responses. F-L-R-Exo can protect the mice from SARS-CoV-2 pseudovirus infection after a challenge. These findings hold great promise for the development of a novel respiratory mucosal vaccine approach.

Author Info: (1) School of Pharmaceutical Sciences & State Key Laboratory of Functions and Applications of Medicinal Plants & Microbiology and Biochemical Pharmaceutical Engineering Research Ce

Author Info: (1) School of Pharmaceutical Sciences & State Key Laboratory of Functions and Applications of Medicinal Plants & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang, 550025, China. Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (2) Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (3) Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (4) Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (5) School of Pharmaceutical Sciences & State Key Laboratory of Functions and Applications of Medicinal Plants & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang, 550025, China. (6) School of Pharmaceutical Sciences & State Key Laboratory of Functions and Applications of Medicinal Plants & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang, 550025, China. Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (7) Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (8) Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (9) Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China. (10) Advanced Research Institute of Multidisciplinary Science, School of Life Science, School of Medical Technology (Institute of Engineering Medicine), Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering Beijing Institute of Technology, Beijing, 100081, China. (11) School of Pharmaceutical Sciences & State Key Laboratory of Functions and Applications of Medicinal Plants & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang, 550025, China. (12) Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China.

Comparison of the Efficacy and Safety of Axi-Cel and Tisa-Cel Based on Meta-Analysis

This study aimed to analyze the efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy for B-cell lymphoma using published literature data. Literature on CAR-T therapy for B-cell lymphoma was collected by searching common databases. The literature was screened, quality assessed, and data extracted according to the inclusion and exclusion criteria. We performed a quantitative meta-analysis of the efficacy and safety of combined literature data. If the data could not be combined, descriptive analysis was performed. The meta-analysis results indicated that compared with tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel) had higher objective response rate (ORR) and complete response rate, with odds ratio (OR) of 0.63 for both sides (95% confidence interval [CI], 0.50-0.79) and statistically significant differences. Partial response rate was lower with axi-cel than with tisa-cel, with an OR of 1.02 for tisa-cel versus axi-cel (95% CI, 0.75-1.40) and no statistically significant difference. Compared with tisa-cel, axi-cel had longer progression-free survival and overall survival, with risk ratios of 0.70 (95% CI, 0.62-0.80) and 0.71 (95% CI, 0.61-0.84) for axi-cel and tisa-cel, respectively. Compared with tisa-cel, axi-cel had higher incidence rates of cytokine release syndrome (CRS) and immune effector cell-related neurotoxicity syndrome (ICANS), with ORs of 3.84 (95% CI, 2.10-7.03) and 4.4 (95% CI, 2.81-6.91), respectively. CAR T-cell therapy is an effective treatment option for relapsed/refractory B-cell lymphoma. Axi-cel has better ORR and survival advantages compared with tisa-cel; however, axi-cel has higher incidence rates of CRS and ICANS compared with tisa-cel.

Author Info: (1) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. State Key Laboratory of Targeting Oncology, Guangxi Medical Univ

Author Info: (1) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning, Guangxi, 530021, China. (2) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Guangxi, Nanning, 530022, China. (3) Department of Pharmacy Foresea Life Insurance Guangxi Hospital, Nanning, Guangxi, 530200, China. (4) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (5) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (6) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (7) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (8) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (9) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (10) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (11) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (12) College of Oncology, Guangxi Medical University,Nanning, Guangxi, 530021, China. (13) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China. (14) Department of Hematology/Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, China.

mRNA vaccines: a new era in vaccine development

The advent of RNA therapy, particularly through the development of mRNA cancer vaccines, has ushered in a new era in the field of oncology. This article provides a concise overview of the key principles, recent advancements, and potential implications of mRNA cancer vaccines as a groundbreaking modality in cancer treatment. mRNA cancer vaccines represent a revolutionary approach to combatting cancer by leveraging the body's innate immune system. These vaccines are designed to deliver specific mRNA sequences encoding cancer-associated antigens, prompting the immune system to recognize and mount a targeted response against malignant cells. This personalized and adaptive nature of mRNA vaccines holds immense potential for addressing the heterogeneity of cancer and tailoring treatments to individual patients. Recent breakthroughs in the development of mRNA vaccines, exemplified by the success of COVID-19 vaccines, have accelerated their application in oncology. The mRNA platform's versatility allows for the rapid adaptation of vaccine candidates to various cancer types, presenting an agile and promising avenue for therapeutic intervention. Clinical trials of mRNA cancer vaccines have demonstrated encouraging results in terms of safety, immunogenicity, and efficacy. Pioneering candidates, such as BioNTech's BNT111 and Moderna's mRNA-4157, have exhibited promising outcomes in targeting melanoma and solid tumors, respectively. These successes underscore the potential of mRNA vaccines to elicit robust and durable anti-cancer immune responses. While the field holds great promise, challenges such as manufacturing complexities and cost considerations need to be addressed for widespread adoption. The development of scalable and cost-effective manufacturing processes, along with ongoing clinical research, will be pivotal in realizing the full potential of mRNA cancer vaccines. Overall, mRNA cancer vaccines represent a cutting-edge therapeutic approach that holds the promise of transforming cancer treatment. As research progresses, addressing challenges and refining manufacturing processes will be crucial in advancing these vaccines from clinical trials to mainstream oncology practice, offering new hope for patients in the fight against cancer.

Author Info: (1) School of Pharmacy & Medical Sciences, Gold Coast campus, Griffith University, Brisbane, QLD-4222, Australia. Menzies Health Institute Queensland (MHIQ), Gold Coast Campus, Gri

Author Info: (1) School of Pharmacy & Medical Sciences, Gold Coast campus, Griffith University, Brisbane, QLD-4222, Australia. Menzies Health Institute Queensland (MHIQ), Gold Coast Campus, Griffith University, Brisbane, QLD-4215, Australia. (2) School of Pharmacy & Medical Sciences, Gold Coast campus, Griffith University, Brisbane, QLD-4222, Australia. Menzies Health Institute Queensland (MHIQ), Gold Coast Campus, Griffith University, Brisbane, QLD-4215, Australia. (3) School of Allied Health, Australian Catholic University, Brisbane, QLD-4014, Australia. (4) School of Pharmacy & Medical Sciences, Gold Coast campus, Griffith University, Brisbane, QLD-4222, Australia. Menzies Health Institute Queensland (MHIQ), Gold Coast Campus, Griffith University, Brisbane, QLD-4215, Australia.

Designed endocytosis-inducing proteins degrade targets and amplify signals

Endocytosis and lysosomal trafficking of cell surface receptors can be triggered by endogenous ligands. Therapeutic approaches such as lysosome-targeting chimaeras(1,2) (LYTACs) and cytokine receptor-targeting chimeras(3) (KineTACs) have used this to target specific proteins for degradation by fusing modified native ligands to target binding proteins. Although powerful, these approaches can be limited by competition with native ligands and requirements for chemical modification that limit genetic encodability and can complicate manufacturing, and, more generally, there may be no native ligands that stimulate endocytosis through a given receptor. Here we describe computational design approaches for endocytosis-triggering binding proteins (EndoTags) that overcome these challenges. We present EndoTags for insulin-like growth factor 2 receptor (IGF2R) and asialoglycoprotein receptor (ASGPR), sortilin and transferrin receptors, and show that fusing these tags to soluble or transmembrane target protein binders leads to lysosomal trafficking and target degradation. As these receptors have different tissue distributions, the different EndoTags could enable targeting of degradation to different tissues. EndoTag fusion to a PD-L1 antibody considerably increases efficacy in a mouse tumour model compared to antibody alone. The modularity and genetic encodability of EndoTags enables AND gate control for higher-specificity targeted degradation, and the localized secretion of degraders from engineered cells. By promoting endocytosis, EndoTag fusion increases signalling through an engineered ligand-receptor system by nearly 100-fold. EndoTags have considerable therapeutic potential as targeted degradation inducers, signalling activators for endocytosis-dependent pathways, and cellular uptake inducers for targeted antibody-drug and antibody-RNA conjugates.

Author Info: (1) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Department of Bioengineering,

Author Info: (1) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Department of Bioengineering, University of Washington, Seattle, WA, USA. (2) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (3) Department of Chemistry, Stanford University, Stanford, CA, USA. (4) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. (5) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (6) Instituto de Medicina Molecular Jo‹o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. (7) Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. (8) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (9) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (10) Institute for Protein Design, University of Washington, Seattle, WA, USA. (11) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. (12) Institute for Protein Design, University of Washington, Seattle, WA, USA. (13) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (14) Institute for Protein Design, University of Washington, Seattle, WA, USA. (15) Institute for Protein Design, University of Washington, Seattle, WA, USA. (16) Institute for Protein Design, University of Washington, Seattle, WA, USA. (17) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (18) Novo Nordisk, MŒl¿v, Denmark. (19) Novo Nordisk, MŒl¿v, Denmark. (20) Novo Nordisk, MŒl¿v, Denmark. (21) Novo Nordisk, MŒl¿v, Denmark. (22) Novo Nordisk, MŒl¿v, Denmark. (23) Departments of Biomedical Engineering and Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (24) Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. (25) Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. (26) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (27) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (28) Institute for Protein Design, University of Washington, Seattle, WA, USA. (29) Institute for Protein Design, University of Washington, Seattle, WA, USA. (30) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (31) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (32) Hubrecht Institute, Utrecht, The Netherlands. (33) Institute for Protein Design, University of Washington, Seattle, WA, USA. (34) Harvard Medical School, Harvard University, Boston, MA, USA. (35) Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA, USA. (36) School of Life Sciences, Westlake University, Hangzhou, China. (37) Institute for Protein Design, University of Washington, Seattle, WA, USA. (38) Institute for Protein Design, University of Washington, Seattle, WA, USA. (39) Novo Nordisk, MŒl¿v, Denmark. (40) Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. (41) Novo Nordisk, MŒl¿v, Denmark. (42) Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. (43) Instituto de Medicina Molecular Jo‹o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. (44) Department of Chemistry, Stanford University, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford, CA, USA. Sarafan ChEM-H, Stanford University, Stanford, CA, USA. (45) Department of Biochemistry, University of Washington, Seattle, WA, USA. dabaker@uw.edu. Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. dabaker@uw.edu.

Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

Author Info: (1) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Graduate School of Medic

Author Info: (1) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (2) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (3) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (4) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (5) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (6) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (7) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (8) Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. (9) Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. (10) Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Polymeric PD1/PDL1 bispecific antibody enhances immune checkpoint blockade therapy

Immune checkpoint blockade (ICB) therapy, particularly PD1/PDL1 inhibition, has demonstrated success in bolstering durable responses in patients. However, the response rate remains below 30 %. In this study, we developed a polymeric bispecific antibody (BsAb) targeting PD1/PDL1 to enhance ICB therapy. Specifically, poly((L)-glutamic acid) (PGLU) was conjugated with a double cyclic Fc binding peptide, Fc-III-4C, through condensation reactions between the -COOH group of PGLU and the -NH(2) group of Fc-III-4C. This conjugate was then mixed with _PD1 and _PDL1 monoclonal antibodies (mAbs) in an aqueous solution. Mechanistically, the PD1/PDL1 BsAb (BsAb(_PD1+_PDL1)) acts as a bridge between tumor cells and CD8(+) T cells, continuously activating CD8(+) T cells to a greater extent. This leads to significantly suppressed tumor growth and prolonged survival in a mouse model of colon cancer compared to treatment with either a single mAb or a mixture of free mAbs. The tumor suppression rate achieved by the BsAb(_PD1+_PDL1) was 90.1 %, with a corresponding survival rate of 83.3 % after 48 days. Thus, this study underscores the effectiveness of the BsAb(_PD1+_PDL1) as a synchronizing T cell engager and dual ICBs, offering theoretical guidance for clinical ICB therapy.

Author Info: (1) Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China. (2) Key Laboratory of Polymer Ecomaterials, Changchun Institu

Author Info: (1) Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China. (2) Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China. (3) Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China. (4) Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China. (5) Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China. (6) Key Laboratory of UV-Emitting Materials and Technology, Northeast Normal University, Ministry of Education, Changchun, Jilin, 130024, China. (7) Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China. (8) Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China.

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