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1.
Nature ; 626(7999): 626-634, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38326614

ABSTRACT

Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function1. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11-PIK3R3, found in a CD4+ cutaneous T cell lymphoma2, that augments CARD11-BCL10-MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.


Subject(s)
Evolution, Molecular , Immunotherapy, Adoptive , Lymphoma, T-Cell, Cutaneous , Mutation , T-Lymphocytes , Humans , CARD Signaling Adaptor Proteins/genetics , CARD Signaling Adaptor Proteins/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cytokines/biosynthesis , Cytokines/immunology , Cytokines/metabolism , Guanylate Cyclase/genetics , Guanylate Cyclase/metabolism , Immunotherapy, Adoptive/methods , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Cutaneous/therapy , Phosphatidylinositol 3-Kinases , Signal Transduction/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/transplantation
2.
Sci Transl Med ; 14(670): eabm1463, 2022 11 09.
Article in English | MEDLINE | ID: mdl-36350984

ABSTRACT

Chimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers but have shown limited efficacy in persistent, recurrent malignancies. Here, we introduce "CAR Pooling," a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with signaling domains derived from a range of immune cell lineages were evaluated in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several domains were identified from the tumor necrosis factor (TNF) receptor family that have been primarily associated with B cells. CD40 enhanced proliferation, whereas B cell-activating factor receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI) promoted cytotoxicity. These functions were enhanced relative to clinical benchmarks after prolonged antigen stimulation, and CAR T cell signaling through these domains fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic transcriptional signature previously associated with positive clinical outcomes. We also observed that replacing the 4-1BB intracellular signaling domain with the BAFF-R signaling domain in a clinically validated B cell maturation antigen (BCMA)-specific CAR resulted in enhanced activity in a xenotransplant model of multiple myeloma. Together, these results show that CAR Pooling is a general approach for rapid exploration of CAR architecture and activity to improve the efficacy of CAR T cell therapies.


Subject(s)
Neoplasm Recurrence, Local , Receptors, Chimeric Antigen , Humans , Neoplasm Recurrence, Local/metabolism , B-Cell Maturation Antigen , Receptors, Chimeric Antigen/metabolism , Immunotherapy, Adoptive/methods , T-Lymphocytes , Immunotherapy , Signal Transduction
4.
Mol Cell ; 77(4): 709-722.e7, 2020 02 20.
Article in English | MEDLINE | ID: mdl-31932165

ABSTRACT

Bacteria are continually challenged by foreign invaders, including bacteriophages, and have evolved a variety of defenses against these invaders. Here, we describe the structural and biochemical mechanisms of a bacteriophage immunity pathway found in a broad array of bacteria, including E. coli and Pseudomonas aeruginosa. This pathway uses eukaryotic-like HORMA domain proteins that recognize specific peptides, then bind and activate a cGAS/DncV-like nucleotidyltransferase (CD-NTase) to generate a cyclic triadenylate (cAAA) second messenger; cAAA in turn activates an endonuclease effector, NucC. Signaling is attenuated by a homolog of the AAA+ ATPase Pch2/TRIP13, which binds and disassembles the active HORMA-CD-NTase complex. When expressed in non-pathogenic E. coli, this pathway confers immunity against bacteriophage λ through an abortive infection mechanism. Our findings reveal the molecular mechanisms of a bacterial defense pathway integrating a cGAS-like nucleotidyltransferase with HORMA domain proteins for threat sensing through protein detection and negative regulation by a Trip13 ATPase.


Subject(s)
ATPases Associated with Diverse Cellular Activities/metabolism , Bacterial Proteins/metabolism , Escherichia coli/virology , Nucleotidyltransferases/metabolism , ATPases Associated with Diverse Cellular Activities/chemistry , Bacterial Proteins/chemistry , Bacteriophage lambda/physiology , Deoxyribonuclease I/metabolism , Escherichia coli/immunology , Escherichia coli/metabolism , Nucleotidyltransferases/chemistry , Peptides/metabolism , Second Messenger Systems
5.
Curr Opin Immunol ; 59: 79-87, 2019 08.
Article in English | MEDLINE | ID: mdl-31071513

ABSTRACT

T lymphocyte and other cell therapies have the potential to transform how we treat cancers and other diseases that have few therapeutic options. Here, we review the current progress in engineered T cell therapies and look to the future of what will establish cell therapy as the next pillar of medicine. The tools of synthetic biology along with fundamental knowledge in cell biology and immunology have enabled the development of approaches to engineer cells with enhanced capacity to recognize and treat disease safely and effectively. This along with new modes of engineering cells with CRISPR and strategies to make universal 'off-the-shelf' cell therapies will provide more rapid, flexible, and cheaper translation to the clinic.


Subject(s)
Cancer Vaccines/immunology , Immune System Diseases/therapy , Immunotherapy, Adoptive/methods , Neoplasms/therapy , T-Lymphocytes/immunology , Animals , Autoimmunity , Bioengineering , Clustered Regularly Interspaced Short Palindromic Repeats , Humans , Immune System Diseases/immunology , Neoplasms/immunology , T-Lymphocytes/transplantation
6.
J Clin Invest ; 128(10): 4654-4668, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30198904

ABSTRACT

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.


Subject(s)
B7-H1 Antigen/immunology , Immunotherapy , Killer Cells, Natural/immunology , Neoplasms, Experimental/therapy , Programmed Cell Death 1 Receptor/immunology , Animals , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , Humans , K562 Cells , Killer Cells, Natural/pathology , Mice , Mice, Knockout , Neoplasms, Experimental/genetics , Neoplasms, Experimental/pathology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics
7.
J Clin Invest ; 124(11): 4781-94, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25329698

ABSTRACT

Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I-deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I-deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.


Subject(s)
Interleukin-12/pharmacology , Interleukin-18/pharmacology , Interleukin-2/pharmacology , Killer Cells, Natural/immunology , Animals , Antigens, Neoplasm/genetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Clonal Anergy , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/metabolism , Humans , Immunotherapy , Killer Cells, Natural/drug effects , Major Histocompatibility Complex/genetics , Mice, Inbred C57BL , Neoplasm Transplantation , Tumor Escape , Xenograft Model Antitumor Assays
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