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1.
Nature ; 627(8004): 646-655, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38418879

RESUMO

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.


Assuntos
Anticorpos Monoclonais , Antineoplásicos , Antígeno B7-H1 , Células Mieloides , Neoplasias , Receptores Imunológicos , Linfócitos T Reguladores , Animais , Humanos , Camundongos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Quimioterapia Combinada , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Ativação de Macrófagos , Células Mieloides/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptores de IgG/imunologia , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia
5.
J Immunol ; 203(4): 1076-1087, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31253728

RESUMO

Elicitation of tumor cell killing by CD8+ T cells is an effective therapeutic approach for cancer. In addition to using immune checkpoint blockade to reinvigorate existing but unresponsive tumor-specific T cells, alternative therapeutic approaches have been developed, including stimulation of polyclonal T cell cytolytic activity against tumors using bispecific T cell engager (BiTE) molecules that simultaneously engage the TCR complex and a tumor-associated Ag. BiTE molecules are efficacious against hematologic tumors and are currently being explored as an immunotherapy for solid tumors. To understand mechanisms regulating BiTE molecule--mediated CD8+ T cell activity against solid tumors, we sought to define human CD8+ T cell populations that efficiently respond to BiTE molecule stimulation and identify factors regulating their cytolytic activity. We find that human CD45RA+CCR7- CD8+ T cells are highly responsive to BiTE molecule stimulation, are enriched in genes associated with cytolytic effector function, and express multiple unique inhibitory receptors, including leukocyte Ig-like receptor B1 (LILRB1). LILRB1 and programmed cell death protein 1 (PD1) were found to be expressed by distinct CD8+ T cell populations, suggesting different roles in regulating the antitumor response. Engaging LILRB1 with its ligand HLA-G on tumor cells significantly inhibited BiTE molecule-induced CD8+ T cell activation. Blockades of LILRB1 and PD1 induced greater CD8+ T cell activation than either treatment alone. Together, our data suggest that LILRB1 functions as a negative regulator of human CD8+ effector T cells and that blocking LILRB1 represents a unique strategy to enhance BiTE molecule therapeutic activity against solid tumors.


Assuntos
Anticorpos Biespecíficos/farmacologia , Antígenos CD/imunologia , Imunoterapia/métodos , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Anticorpos Biespecíficos/imunologia , Humanos , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/antagonistas & inibidores , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Células Tumorais Cultivadas
7.
Cell Rep Med ; 5(2): 101393, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38280376

RESUMO

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.


Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Humanos , Carboplatina/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/induzido quimicamente , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Desoxicitidina/uso terapêutico , Gencitabina , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/induzido quimicamente , Neoplasias Urológicas/patologia
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