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1.
Nat Immunol ; 23(6): 904-915, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35618834

RESUMEN

Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8+ T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.


Asunto(s)
Neoplasias de la Mama , Interleucina-15/metabolismo , Animales , Neoplasias de la Mama/genética , Linfocitos T CD8-positivos , Femenino , Granzimas , Humanos , Inmunidad Innata , Linfocitos , Ratones
2.
Cell ; 164(3): 365-77, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26806130

RESUMEN

Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αß, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells.


Asunto(s)
Linfocitos/inmunología , Neoplasias Mamarias Experimentales/inmunología , Monitorización Inmunológica , Subgrupos de Linfocitos T/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Granzimas/metabolismo , Interleucina-15/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo
4.
Nature ; 605(7908): 139-145, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35444279

RESUMEN

Cellular transformation induces phenotypically diverse populations of tumour-infiltrating T cells1-5, and immune checkpoint blockade therapies preferentially target T cells that recognize cancer cell neoantigens6,7. Yet, how other classes of tumour-infiltrating T cells contribute to cancer immunosurveillance remains elusive. Here, in a survey of T cells in mouse and human malignancies, we identified a population of αß T cell receptor (TCR)-positive FCER1G-expressing innate-like T cells with high cytotoxic potential8 (ILTCKs). These cells were broadly reactive to unmutated self-antigens, arose from distinct thymic progenitors following early encounter with cognate antigens, and were continuously replenished by thymic progenitors during tumour progression. Notably, expansion and effector differentiation of intratumoural ILTCKs depended on interleukin-15 (IL-15) expression in cancer cells, and inducible activation of IL-15 signalling in adoptively transferred ILTCK progenitors suppressed tumour growth. Thus, the antigen receptor self-reactivity, unique ontogeny, and distinct cancer cell-sensing mechanism distinguish ILTCKs from conventional cytotoxic T cells, and define a new class of tumour-elicited immune response.


Asunto(s)
Inmunidad Innata , Interleucina-15 , Neoplasias , Animales , Diferenciación Celular , Ratones , Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Citotóxicos/metabolismo
5.
Nature ; 529(7587): 532-6, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26789248

RESUMEN

Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.


Asunto(s)
Autoinmunidad/inmunología , Linfocitos T CD8-positivos/inmunología , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica/inmunología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Diferenciación Celular , Movimiento Celular/inmunología , Regulación hacia Abajo , Femenino , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Ratones , Mutación , Fosforilación , Transducción de Señal/inmunología , Linfocitos T Reguladores/citología , Transcripción Genética
6.
Sci Immunol ; 7(70): eabi8642, 2022 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-35394814

RESUMEN

Innate lymphocytes are integral components of the cellular immune system that can coordinate host defense against a multitude of challenges and trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we showed that the cytolytic molecule granzyme C was expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C-expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s. These granzyme C-expressing ILC1s required the transcription factors T-bet and, to a lesser extent, Eomes and support from transforming growth factor-ß (TGF-ß) signaling for their maintenance in the salivary gland. In a transgenic mouse breast cancer model, depleting ILC1s caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Constitutive activation of STAT5, a transcription factor regulated by IL-15, in granzyme C-expressing ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond "helper-like" lymphocytes.


Asunto(s)
Inmunidad Innata , Interleucina-15 , Animales , Autoinmunidad , Granzimas , Células Asesinas Naturales , Ratones , Perforina
7.
Adv Exp Med Biol ; 650: 180-94, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19731811

RESUMEN

The majority of haematological cancers involve the lymphoid system. They include acute lymphoblastic leukemias (ALL), which are arrested at variable stages of development and present with blood and bone marrow involvement and chronic leukemias, lymphomas and myelomas, which present with infiltration of a large variety of hematopoietic and non hematopoietic tissues by mature lymphoid cells which express a surface antigen receptor. The majority involve the B-cell lineage and the vast majority have undergone clonal rearrangement of their Ig and/or TCR rearrangements. Analysis of Ig/TCR genomic V(D)J repertoires by PCR based lymphoid clonality analysis within a diagnostic setting allows distinction of clonal from reactive lymphoproliferative disorders, clonal tracking for evidence of tumor dissemination and follow-up, identification of a lymphoid origin in undiagnosed tumors and evaluation of clonal evolution. Ig/TCR VDJ errors are also at the origin of recombinase mediated deregulated expression of a variety of proto-oncogenes in ALL, whereas in lymphoma it is increasingly clear that IgH containing translocations result from abnormalities other than VDJ errors (somatic hypermutation and/or isotype switching). In addition to this mechanistic contribution to lymphoid oncogenesis, it is possible that failure to successfully complete expression of an appropriate Ig or TCR may lead to maturation arrest in a lymphoid precursor, which may in itself contribute to altered tissue homeostasis, particularly if the arrest occurs at a stage of cellular expansion.


Asunto(s)
Reordenamiento Génico de Linfocito B , Reordenamiento Génico de Linfocito T , Neoplasias Hematológicas , Trastornos Linfoproliferativos , Recombinación Genética , Genes de Inmunoglobulinas , Genes Codificadores de los Receptores de Linfocitos T , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Humanos , Fenómenos del Sistema Inmunológico , Inmunoglobulinas/genética , Inmunoglobulinas/inmunología , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , VDJ Recombinasas/metabolismo
8.
J Immunother Cancer ; 5: 41, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28515941

RESUMEN

Tumor cells can be detected and cleared by lymphocytes in a process termed cancer immunosurveillance. However, the contributing cell types had not been fully characterized. Using oncogene-induced murine models of epithelial cancer, a recent study showed that cell transformation triggers expansion of tissue-resident lymphocytes derived from innate, T cell receptor (TCR) αß and TCRγδ lineages. These type-1-like innate lymphoid cells (ILC1ls) and type 1 innate-like T cells (ILTC1s) share a gene expression program distinct from those of conventional lymphocytes, and exhibit cytolytic activities against tumor cells. Further deciphering such a tumor-elicited immunosurveillance mechanism may 1 day be harnessed for novel cancer immunotherapy.


Asunto(s)
Neoplasias , Linfocitos T/inmunología , Animales , Humanos , Linfocitos/inmunología , Ratones , Monitorización Inmunológica , Receptores de Antígenos de Linfocitos T alfa-beta/genética
9.
Cancer Cell ; 21(4): 563-76, 2012 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-22516263

RESUMEN

Acute lymphoblastic leukemias (ALLs) are characterized by multistep oncogenic processes leading to cell-differentiation arrest and proliferation. Specific abrogation of maturation blockage constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. TLX1/TLX3 abrogation or enforced TCRαß expression leads to TCRα rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCRα-driven TLX1 expression supports TLX "addiction" in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T , Proteínas de Homeodominio/fisiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteína Proto-Oncogénica c-ets-1/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Apoptosis , Sitios de Unión , Reordenamiento Génico , Células HeLa , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Estructura Terciaria de Proteína , Proteína Proto-Oncogénica c-ets-1/fisiología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo
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