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1.
Immunity ; 56(1): 143-161.e11, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630913

RESUMO

Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.


Assuntos
Interleucinas , Neoplasias , Receptores Virais , Linfócitos T Auxiliares-Indutores , Animais , Humanos , Camundongos , Antígenos de Diferenciação de Linfócitos T/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Células Matadoras Naturais/metabolismo , Neoplasias/metabolismo , Ligação Proteica , Linfócitos T Auxiliares-Indutores/metabolismo , Interleucina 22
2.
Nature ; 629(8011): 417-425, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38658748

RESUMO

Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.


Assuntos
Linfócitos T CD8-Positivos , Proliferação de Células , Dinoprostona , Linfócitos do Interstício Tumoral , Neoplasias , Células-Tronco , Evasão Tumoral , Animais , Feminino , Humanos , Masculino , Camundongos , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Dinoprostona/metabolismo , Modelos Animais de Doenças , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Interleucina-2 , Linfonodos/citologia , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/prevenção & controle , Receptores de Prostaglandina E Subtipo EP2/deficiência , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/deficiência , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Evasão Tumoral/imunologia
3.
Br J Cancer ; 127(12): 2175-2185, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36266575

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has been successfully translated to clinical practice for the treatment of B cell malignancies. The suppressive microenvironment of many malignancies is a bottleneck preventing treatment success of CAR T cells in a broader range of tumours. Among others, the immunosuppressive metabolite adenosine is present in high concentrations within many tumours and dampens anti-tumour function of immune cells and consequently therapeutic response. METHODS: Here, we present the impact of the selective adenosine A2A and A2B receptor antagonist AB928/etrumadenant on CAR T cell cytokine secretion, proliferation, and cytotoxicity. Using phosphorylation-specific flow cytometry, we evaluated the capability of AB928 to shield CAR T cells from adenosine-mediated signalling. The effect of orally administered AB928 on CAR T cells was assessed in a syngeneic mouse model of colon carcinoma. RESULTS: We found that immunosuppressive signalling in CAR T cells in response to adenosine was fully blocked by the small molecule inhibitor. AB928 treatment enhanced CAR T cell cytokine secretion and proliferation, granted efficient cytolysis of tumour cells in vitro and augmented CAR T cell activation in vivo. CONCLUSIONS: Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy.


Assuntos
Neoplasias , Linfócitos T , Animais , Camundongos , Adenosina/farmacologia , Citocinas , Microambiente Tumoral
4.
Nat Commun ; 14(1): 6858, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37891230

RESUMO

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.


Assuntos
Glicólise , Neoplasias , Animais , Camundongos , Linfócitos T CD8-Positivos , Neoplasias/terapia , Mitocôndrias , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
5.
STAR Protoc ; 3(4): 101708, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36136753

RESUMO

A major impediment to effective cellular therapies in solid tumors is the limited access of therapeutic cells to the tumor site. One strategy to overcome this challenge is to endow T cells with chemotactic properties required to access tumor tissue. Here, we present a chimeric antigen receptor (CAR)-modified T cell strategy centered around enhanced T cell trafficking. We outline isolation, activation, and transduction of human T cells, as well as techniques for assessing migratory and cytotoxic capacity of CAR-T cells. For complete details on the use and execution of this protocol, please refer to Lesch et al. (2021).


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/métodos , Quimiotaxia , Neoplasias/terapia , Linfócitos T
6.
Leukemia ; 35(8): 2243-2257, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33414484

RESUMO

Targeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.


Assuntos
Imunoterapia Adotiva/métodos , Leucemia Experimental/terapia , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/transplante , Animais , Feminino , Humanos , Leucemia Experimental/imunologia , Leucemia Experimental/patologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Linfócitos T/imunologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Sci Adv ; 7(24)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34108220

RESUMO

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor-ß (TGF-ß). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-ß receptor 2 (DNR) can simultaneously shield them from TGF-ß. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-ß shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.


Assuntos
Neoplasias , Humanos , Neoplasias/terapia , Linfócitos T Reguladores , Fator de Crescimento Transformador beta/farmacologia
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