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1.
Cancer Immunol Res ; 10(11): 1354-1369, 2022 11 02.
Article in English | MEDLINE | ID: mdl-36095236

ABSTRACT

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T-produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.


Subject(s)
Receptors, Chimeric Antigen , T-Lymphocytes , Animals , Mice , Antigens, Neoplasm , Cell Line, Tumor , Disease Models, Animal , Immunotherapy, Adoptive , Macrophages/metabolism , Receptors, Chimeric Antigen/metabolism , Xenograft Model Antitumor Assays , Disease Progression
2.
Cell ; 185(7): 1223-1239.e20, 2022 03 31.
Article in English | MEDLINE | ID: mdl-35290801

ABSTRACT

While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T cells excluded, concomitant with upregulated TGFß and TGFß-mediated fibroblast activation, indicating that TGFß-receptor loss on cancer cells increased TGFß bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGFß responsiveness of cancer cells can affect the TME.


Subject(s)
Neoplasms , Tumor Microenvironment , Animals , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Genomics , Mice , Neoplasms/genetics , Transforming Growth Factor beta/genetics
3.
Nat Rev Immunol ; 22(3): 144, 2022 03.
Article in English | MEDLINE | ID: mdl-35082449
4.
Nat Rev Immunol ; 20(10): 591, 2020 10.
Article in English | MEDLINE | ID: mdl-32807861
5.
Immunity ; 52(6): 910-941, 2020 06 16.
Article in English | MEDLINE | ID: mdl-32505227

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Animals , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Disease Susceptibility , Humans , Immunity, Innate , Immunologic Memory , Inflammation/immunology , Inflammation/virology , Lymphocytes/immunology , Myeloid Cells/immunology , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , SARS-CoV-2
6.
Nat Rev Immunol ; 20(6): 353, 2020 06.
Article in English | MEDLINE | ID: mdl-32355329
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