TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+ T cell and XCR1+ dendritic cell spatial co-localization.
J Immunother Cancer
; 10(1)2022 01.
Article
em En
| MEDLINE
| ID: mdl-34987021
ABSTRACT
BACKGROUND:
T cell immunoglobulin and mucin domain containing-3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.METHODS:
T cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.RESULTS:
TIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.CONCLUSIONS:
TIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tratamento
Base de dados:
MEDLINE
Assunto principal:
Células Dendríticas
/
Interleucina-12
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Linfócitos T CD8-Positivos
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Receptores de Quimiocinas
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Receptor Celular 2 do Vírus da Hepatite A
/
Imunoterapia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Immunother Cancer
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos