Journal Articles

Immune checkpoint blockade facilitates primary tumor rejection in a cDC1-independent manner without immunological memory acquisition

Author Info: 1. Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 2. Department of Respiratory Medicine, Faculty of Medici

Author Info: 1. Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 2. Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan 3. Department of Medical Oncology, Shinshu Cancer Center, Shinshu University Hospital, Matsumoto, Japan 4. Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan 5. Department of Medical Oncology, Hokkaido University Hospital, Sapporo, Japan 6. Division of Clinical Cancer Genomics, Hokkaido University Hospital, Sapporo, Japan 7. Quantum immunology Team, Institute for Quantum Life science, National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan 8. Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan 9. Institute for Vaccine Research and Development, Hokkaido University, Sapporo 001-0021, Japan

Antigen presentation requirements for effective cDC1-based cancer immunotherapy

Type 1 conventional dendritic cells (cDC1s) are important for generating and sustaining antitumor immunity. Accordingly, the abundance of cDC1s in human tumors correlates with improved outcomes in cancer. Capitalizing on this role, we previously demonstrated that vaccination with murine cDC1s, generated in culture from bone marrow cells (termed here "in vitro-derived cDC1s"), elicits durable tumor control in multiple preclinical models; however, the immunological mechanisms underlying the efficacy of cDC1 vaccination remain unclear. Here, we examined whether in vitro-derived cDC1s resemble tumor-infiltrating DC populations and whether MHC-I and MHC-II antigen presentation contribute to cDC1-mediated tumor control following vaccination in melanoma. As expected, MHC-I or MHC-II deficiency had minimal impact on the transcriptional state of cDC1s in homeostasis or following stimulation with the adjuvant poly dI:dC. Moreover, in vitro-derived cDC1s cultured under steady-state conditions closely resembled tumor-infiltrating cDC1s, whereas their poly dI:dC-stimulated counterparts resembled CCR7+ tumor-infiltrating DC populations, also referred to as mregDCs or LAMP3+ DCs. Our data further show that both MHC-I and MHC-II contribute to tumor control upon cDC1 vaccination and that coexpression of MHC-I and MHC-II on the same cDC1 is necessary for a robust vaccine response. We also identified an important function for host cDC1s in supporting the efficacy of vaccination with in vitro-derived cDC1s, as judged by impaired tumor control in Irf8_+_32-/- mice, which lack endogenous cDC1s. Overall, these results indicate that effective antitumor responses depend on MHC-I and MHC-II antigen presentation by vaccine-delivered cDC1s, with additional contributions from host cDC1s.

Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The Univer

Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (3) Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (5) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (6) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (7) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (8) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (9) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (10) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (11) Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (12) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (13) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. MD Anderson UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

In vivo genome-wide CRISPR screens of human T cells in solid tumours

Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that enhance cellular immunotherapy. Yet, many regulators of T cell performance in solid tumours are not revealed in vitro(1,2). In vivo screening in tumour-bearing mice is more physiological but has been limited by low intratumoural T cell recovery. Here we developed an in vivo model that efficiently recovers human T cells from solid tumours, permitting genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model exhibit hallmarks of dysfunction compared with splenic T cells, creating an ideal screening context. We performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. The abundance screen revealed the P2RY8-G_13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The effector function screen identified GNAS as a key driver of T cell dysfunction in tumours, whose product, G_s, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across diverse solid tumour models in chimeric antigen receptor (CAR) and T cell receptor (TCR) systems. Combinatorial knockout of P2RY8-GNAS further enhanced tumour control, demonstrating that complementary in vivo screens can identify orthogonal targets whose combined editing improves therapeutic potency. This flexible, scalable platform can be adapted for systematic discovery of genetic strategies to improve solid tumour T cell therapies.

Author Info: (1) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. qi.liu3@ucsf.edu. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA

Author Info: (1) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. qi.liu3@ucsf.edu. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. qi.liu3@ucsf.edu. (2) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (3) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (4) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (5) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (6) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (7) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (8) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. UCSF CoLabs, University of California San Francisco, San Francisco, CA, USA. Department of Surgery, University of California San Francisco, San Francisco, CA, USA. Diabetes Center, University of California San Francisco, San Francisco, CA, USA. (9) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (10) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (11) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (12) Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. (13) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (14) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (15) Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. Division of Pediatric Rheumatology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA. (16) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. (17) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (18) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. (19) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (20) Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. (21) Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (22) Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA. Division of Computational Medicine, Department of Medicine, Stanford University, Stanford, CA, USA. (23) Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA. Division of Computational Medicine, Department of Medicine, Stanford University, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. (24) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. (25) Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. Dotan Center for Advanced Therapies, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (26) Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. Department of Pathology, University of California San Francisco, San Francisco, CA, USA. (27) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. (28) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. (29) Department of OB/Gyn, Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA. (30) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (31) Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. (32) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. Institute for Human Genetics (IHG), University of California San Francisco, San Francisco, CA, USA. Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. Innovative Genomics Institute, University of California Berkeley, Berkeley, CA, USA. (33) Department of Medicine, University of California San Francisco, San Francisco, CA, USA. julia.carnevale@ucsf.edu. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. julia.carnevale@ucsf.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. julia.carnevale@ucsf.edu. Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA. julia.carnevale@ucsf.edu. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. julia.carnevale@ucsf.edu.

A viral-based individualized neoantigen vaccine as adjuvant treatment in resected head and neck squamous cell carcinoma: a randomized Phase I trial

Spotlight 

Ottensmeier and Delord et al. report a randomized phase I trial of adjuvant TG4050, an individualized MVA-vectored neoantigen vaccine encoding up to 30 predicted neoantigens, in high-risk resected HNSCC. TG4050 was feasible and well tolerated, with no relapses among 16 immediately treated patients after 30 months median follow-up, compared to 3 of 16 who relapsed in the control arm. Neoantigen-specific T cell responses (median of 3 neoantigens per responder) occurred in 73.3% of treated patients and persisted for over one year. Vaccine-reactive CD8+ T cells were polyclonal, cytotoxic, and tissue-resident-like, comprising de novo and expanded pre-existing clones.

Contributed by Shishir Pant

Ottensmeier and Delord et al. report a randomized phase I trial of adjuvant TG4050, an individualized MVA-vectored neoantigen vaccine encoding up to 30 predicted neoantigens, in high-risk resected HNSCC. TG4050 was feasible and well tolerated, with no relapses among 16 immediately treated patients after 30 months median follow-up, compared to 3 of 16 who relapsed in the control arm. Neoantigen-specific T cell responses (median of 3 neoantigens per responder) occurred in 73.3% of treated patients and persisted for over one year. Vaccine-reactive CD8+ T cells were polyclonal, cytotoxic, and tissue-resident-like, comprising de novo and expanded pre-existing clones.

Contributed by Shishir Pant

ABSTRACT: In approximately one third of patients, resected head and neck squamous cell carcinoma will recur. We postulated that the induction of tumor neoantigen-specific T cell responses could prevent relapse. To this end, we developed TG4050, an individualized neoantigen therapeutic vaccine encoding up to 30 patient-specific predicted tumor neoantigens delivered by a Modified Vaccinia Ankara viral vector. We tested adjuvant TG4050 as single agent in a randomized phase I trial comparing treatment with TG4050 immediately after standard of care adjuvant therapy versus watchful waiting and treatment with TG4050 after recurrence (NCT04183166). The primary endpoint was safety, secondary endpoints included feasibility and efficacy, and immunogenicity was exploratory. TG4050 was well tolerated. Of 16 evaluable patients randomized the immediate treatment arm, none relapsed after a median follow-up of 30 months, while 3 of 16 relapsed in the control arm. T cell responses to vaccine neoantigens were detected in 73.3% of patients treated with TG4050 immediately, with a median of 3 neoantigens per responder. These responses were maintained throughout treatment and persisted for over one year after the last dose. Vaccine neoantigen-specific CD8+ T cells had an effector phenotype, displayed high expression of cytotoxic and tissue-resident markers, were polyclonal and comprised both de novo responses and amplification of pre-existing tumor-infiltrating T cell clones. Together, these translational data are consistent with the hypothesis in which single-agent delivery of TG4050 induces long-lasting tumor neoantigen-specific cytotoxic T cell responses that can prevent tumor recurrence.

Author Info:

Author Info:

Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits

Spotlight 

Zhu, Dann, et al. developed a transcriptome-wide and transcription factor genome-wide CRISPRi knockdown perturb-seq platform for human CD4+ T cells to comprehensively identify functional gene networks. Four T cell donors were utilized, and deep single-cell RNAseq was conducted under 3 conditions: resting, 8, and 48 hours after stimulation. Multiple patterns (positive and negative; few or many genes affected), context-specific effects (resting vs. stimulated; Th1 vs. Th2), and complex cytokine regulatory patterns were observed. Integration with GWAS studies confirmed and extended known linkages, and revealed new autoimmune targets.

Contributed by Ed Fritsch

Zhu, Dann, et al. developed a transcriptome-wide and transcription factor genome-wide CRISPRi knockdown perturb-seq platform for human CD4+ T cells to comprehensively identify functional gene networks. Four T cell donors were utilized, and deep single-cell RNAseq was conducted under 3 conditions: resting, 8, and 48 hours after stimulation. Multiple patterns (positive and negative; few or many genes affected), context-specific effects (resting vs. stimulated; Th1 vs. Th2), and complex cytokine regulatory patterns were observed. Integration with GWAS studies confirmed and extended known linkages, and revealed new autoimmune targets.

Contributed by Ed Fritsch

ABSTRACT: Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4(+) T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including previously uncharacterized regulators of cytokine production. Importantly, active regulators and the gene programs they control changed dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of T cell polarization and of age-related phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our study provides a foundational resource and new approaches to decode T cell function and human immune traits.

Author Info: (1) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: ronghui.zhu@gladston

Author Info: (1) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: ronghui.zhu@gladstone.ucsf.edu. (2) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: emmadann@stanford.edu. (3) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (4) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (5) Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. (6) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; University of San Francisco, San Francisco, CA, USA. (7) Department of Genetics, Stanford University, Stanford, CA, USA. (8) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (9) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA. (11) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA. (12) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA. Electronic address: pritch@stanford.edu. (13) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. Electronic address: alex.marson@gladstone.ucsf.edu.

Engineered human iPSC-derived dendritic cells dressed with tumor MHC complexes as a cancer vaccine Spotlight 

Xu et al. identified optimal and reproducible culture and cytokine conditions to create universal, human iPSC-derived DCs lacking HLA (B2m/CTIIA KO) and with a CCR7+ migratory DC phenotype. An exosome-inspired process with tumor cell vesicles was used to cross-dress these DCs with peptide:MHC complexes from tumor cells. Cross-dressing promoted antigen presentation and resistance to “non-self” killing by NK cells. With cell lines in vitro and in vivo, the cross-dressed DCs enhanced T cell cytotoxicity and tumor control. Personal cross-dressed vaccines in AML and ovarian cancer were cytolytic in vitro. PD-L1/2 knockout improved activity.

Contributed by Ed Fritsch

Xu et al. identified optimal and reproducible culture and cytokine conditions to create universal, human iPSC-derived DCs lacking HLA (B2m/CTIIA KO) and with a CCR7+ migratory DC phenotype. An exosome-inspired process with tumor cell vesicles was used to cross-dress these DCs with peptide:MHC complexes from tumor cells. Cross-dressing promoted antigen presentation and resistance to “non-self” killing by NK cells. With cell lines in vitro and in vivo, the cross-dressed DCs enhanced T cell cytotoxicity and tumor control. Personal cross-dressed vaccines in AML and ovarian cancer were cytolytic in vitro. PD-L1/2 knockout improved activity.

Contributed by Ed Fritsch

ABSTRACT: Autologous-derived dendritic cells (DCs) are a promising source for cell-based cancer vaccines. However, their therapeutic potential is challenged by the number and quality produced and the diversity of antigens presented. To address these limitations, we present an approach that involves differentiating universal MHC-deficient human-induced pluripotent stem cells (hiPSCs) into CCR7(+) migratory DCs. These DCs are subsequently "dressed" with the full repertoire of MHC-antigen complexes derived from tumor cell membranes, transforming an allogeneic substrate into a personalized cancer vaccine product. The resulting "TumorDressed" DCs effectively activate T cells against tumor antigens. Their function is diminished when CD80/86 is deleted but significantly enhanced by the loss of PD-L1/2. PD-L1/2-null TumorDressed DCs demonstrate robust priming of anti-tumor T cell-mediated cytotoxicity both in vitro and in vivo, including against primary hematologic and solid tumors with matching patient T cells. These findings provide proof of concept for a universal, scalable, adaptable, and off-the-shelf DC cancer vaccine platform.

Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, Univ

Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (2) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (3) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (4) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (5) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (6) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (7) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (8) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (9) AIVITA Biomedical, Irvine, CA, USA. (10) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (11) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (12) AIVITA Biomedical, Irvine, CA, USA. (13) AIVITA Biomedical, Irvine, CA, USA. (14) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (15) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (16) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (17) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. Electronic address: robert.blelloch@ucsf.edu.

Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors Spotlight 

Zhu and Yu et al. developed and characterized a scalable, feeder-free, high-yield platform that generated allogeneic NY-ESO-1-specific cytotoxic T (AlloESO-T) cells from cord blood-derived hematopoietic stem and progenitor cells. Compared to PBMC-derived TCR-T cells, monospecific AlloESO-T cells showed superior cytotoxicity (with dual TCR and NKR targeting), solid tumor homing, HLA-independence, durable killing persistence (with IL-15), and enhanced efficacy in solid tumor models. AlloESO-T cells, which lack endogenous TCRs, exhibited an improved safety profile and minimal GvHD or /cytokine release syndrome risk in vitro and in vivo.

Contributed by Katherine Turner

Zhu and Yu et al. developed and characterized a scalable, feeder-free, high-yield platform that generated allogeneic NY-ESO-1-specific cytotoxic T (AlloESO-T) cells from cord blood-derived hematopoietic stem and progenitor cells. Compared to PBMC-derived TCR-T cells, monospecific AlloESO-T cells showed superior cytotoxicity (with dual TCR and NKR targeting), solid tumor homing, HLA-independence, durable killing persistence (with IL-15), and enhanced efficacy in solid tumor models. AlloESO-T cells, which lack endogenous TCRs, exhibited an improved safety profile and minimal GvHD or /cytokine release syndrome risk in vitro and in vivo.

Contributed by Katherine Turner

ABSTRACT: Adoptive T cell therapy for solid tumors is limited by autologous manufacturing complexity and, in allogeneic settings, risks including graft-versus-host disease (GvHD), HLA restriction, and donor variability. We develop a scalable, feeder-free platform to differentiate gene-engineered hematopoietic stem and progenitor cells (HSPCs) into allogeneic, NY-ESO-1-specific cytotoxic T ((Allo)ESO-T) cells. Product phenotype, function, tumor homing, and safety are assessed against solid tumor models and benchmarked to peripheral blood mononuclear cell (PBMC)-derived TCR-engineered T cells. (Allo)ESO-T cells display a uniform cytotoxic phenotype, with dual tumor targeting through a transgenic TCR and natural killer receptors. Relative to PBMC-derived counterparts, (Allo)ESO-T cells show superior cytotoxicity, selective solid-tumor homing, durable killing persistence, and resilience to immune evasion. They also maintain low GvHD and cytokine release syndrome risk, while retaining stable hypoimmunogenic features. These findings establish HSPC-derived (Allo)ESO-T cells as an off-the-shelf, mono-specific cytotoxic T cell therapy with scalable manufacturing, enhanced efficacy, and improved safety, which support broad applicability of (Allo)ESO-T cells across solid tumors.

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los A

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (2) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (3) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (4) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (5) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (6) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (7) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (8) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (9) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (10) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (11) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (12) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (13) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (14) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (15) Department of Medicine, Division of Cardiology, UCLA, Los Angeles, CA 90095, USA. (16) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (17) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (18) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (19) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (20) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (21) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. Electronic address: charlie.li@ucla.edu. (22) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.

Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome Featured  

Chen, Pulido, et al. investigated how AIRE expression in tumor cells impacts antitumor immune responses using murine models. Overexpression of AIRE led to higher expression of self-proteins, MHC-I in the context of H-2Kb, and MHC-I-presented epitopes, whereas downregulation led to lower expression. Antitumor immunity could be induced by DC vaccines loaded with cell lysates of AIRE-overexpressing tumor cells, inducing CD8+ and CD4+ T cell responses. Therapeutic AIRE tumor expression could be induced with in vivo delivery of an AAV vector, which was effective in curing mice, and survival time was improved by subsequent ICB.

Chen, Pulido, et al. investigated how AIRE expression in tumor cells impacts antitumor immune responses using murine models. Overexpression of AIRE led to higher expression of self-proteins, MHC-I in the context of H-2Kb, and MHC-I-presented epitopes, whereas downregulation led to lower expression. Antitumor immunity could be induced by DC vaccines loaded with cell lysates of AIRE-overexpressing tumor cells, inducing CD8+ and CD4+ T cell responses. Therapeutic AIRE tumor expression could be induced with in vivo delivery of an AAV vector, which was effective in curing mice, and survival time was improved by subsequent ICB.

ABSTRACT: T-cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue-specific self-antigens for presentation to nave T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of "selfness" at the RNA and protein levels which, when presented on major histocompatibility complexes, shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by re-setting the immunological selfness of cancer cells, this AIRE-mediated immunotherapy 1) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; 2) conferred upon non-immunogenic tumors de novo sensitivity to immune checkpoint blockade; 3) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and 4) lead to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors. Patient RNA-sequencing data showed that expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting our studies have therapeutic translational value.

Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Ro

Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (4) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (5) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (6) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (7) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (8) Vyriad United States. (9) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (10) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (11) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (12) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (13) King's College London London United Kingdom. ROR: https://ror.org/0220mzb33 (14) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (15) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (16) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (17) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03

Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function Spotlight 

Takacsi-Nagy et al. generated a library of synthetic T cell Transcription Factors (sTFs) through combinatorial assembly of AP-1 family TF subdomains. Expressed in CAR-T cells, certain sTFs improved CAR-T persistence/proliferation over natural TFs in a chronic stimulation assay. sTFs induced unique transcriptional and epigenetic T cell states from natural TFs, although their DNA binding sites were conserved. One combination (JUN-FOS-BATF) especially improved cytotoxicity and in vivo persistence. The most impactful subdomains did not correlate with natural expression levels. Recombination of ETS and FOX family TF domains was also effective.

Contributed by Alex Najibi

Takacsi-Nagy et al. generated a library of synthetic T cell Transcription Factors (sTFs) through combinatorial assembly of AP-1 family TF subdomains. Expressed in CAR-T cells, certain sTFs improved CAR-T persistence/proliferation over natural TFs in a chronic stimulation assay. sTFs induced unique transcriptional and epigenetic T cell states from natural TFs, although their DNA binding sites were conserved. One combination (JUN-FOS-BATF) especially improved cytotoxicity and in vivo persistence. The most impactful subdomains did not correlate with natural expression levels. Recombination of ETS and FOX family TF domains was also effective.

Contributed by Alex Najibi

ABSTRACT: Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford Univer

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (2) Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. (4) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (5) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (6) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (8) Program in Immunology, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (9) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA. (11) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (12) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (14) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (15) Department of Pathology, Stanford University, Stanford, CA, USA. (16) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (17) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (18) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (20) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (21) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (22) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: troth@stanford.edu. (23) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.

Tumor-induced dendritic cell deregulation perturbs T cell proliferation and predicts clinical outcome in acute lymphoblastic leukemia Spotlight 

Kumar et al. characterized the transcriptome and proteome of the DC compartment in both pediatric and adult ALL, and demonstrated that DC maturation into functional lineages was disrupted. Proliferation, antigen presentation, and cytokine production were impaired across all residual DC subsets, except progenitor/DC4 fractions, leading to a semi-mature, potentially tolerogenic phenotype with defective T cell priming. MYC overexpression in malignant lymphoblasts partly drove the disruption of DC homeostasis. A stimulated DC transcriptional signature at ALL diagnosis correlated with favorable outcomes in B-ALL, but adverse outcomes in T-ALL.

Contributed by Shishir Pant

Kumar et al. characterized the transcriptome and proteome of the DC compartment in both pediatric and adult ALL, and demonstrated that DC maturation into functional lineages was disrupted. Proliferation, antigen presentation, and cytokine production were impaired across all residual DC subsets, except progenitor/DC4 fractions, leading to a semi-mature, potentially tolerogenic phenotype with defective T cell priming. MYC overexpression in malignant lymphoblasts partly drove the disruption of DC homeostasis. A stimulated DC transcriptional signature at ALL diagnosis correlated with favorable outcomes in B-ALL, but adverse outcomes in T-ALL.

Contributed by Shishir Pant

ABSTRACT: Perturbations in dendritic cells (DCs) in B/T cell acute lymphoblastic leukemia (ALL), their cause(s) and consequence(s) on antileukemia immunity, and patient outcomes remain poorly explored. We find that maturation of DC1-6 subsets is disrupted in children and adults with ALL. Conventional DC1 and DC2 subpopulations are reduced at the expense of the progenitors and the DC4 fractions in ALL. The potential to mature, present antigens, and produce cytokines for initiating T cell surveillance appears to be impaired in every ALL DC subset. Such DC subsets are accordingly unable to induce T cell proliferation compared to DCs from healthy donors. MYC overexpression in ALL cells disrupts DC homeostasis and reduces the ability of DCs to induce T cell proliferation. Predominance of cells with transcriptional signatures typical of "stimulated DCs" predicts favorable clinical outcomes in B-ALL, while it is associated with unfavorable outcomes in T-ALL. Phenotyping DC subsets at ALL diagnosis could thus be valuable in informing treatment outcomes.

Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hop

Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (3) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (4) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (5) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (6) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (7) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (8) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (9) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (10) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (11) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (12) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (13) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; The Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (14) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (15) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (16) Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. (17) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (18) Division of Oncology and Center for Childhood Cancer Research, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. (19) Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (20) Department of Clinical Population and Public Health Sciences, University of Southern California, Los Angeles, CA 91016, USA. (21) Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (22) Schneider Children's Medical Center, Tel Aviv University, Felsenstein Research Institute, Tel Aviv, Israel. (23) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (24) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (25) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: sswaminathan@coh.org.

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