Myeloid-T cell interplay and cell state transitions associated with checkpoint inhibitor response in melanoma.
Med
; 5(7): 759-779.e7, 2024 Jul 12.
Article
em En
| MEDLINE
| ID: mdl-38593812
ABSTRACT
BACKGROUND:
The treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms.METHODS:
We performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III-IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed.FINDINGS:
CPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8+ T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and apoptosis-related gene expression. Consistently, predicted non-responder-enriched myeloid-T/natural killer cell interactions were primarily immunosuppressive, while responder-enriched interactions were supportive of T cell priming and effector function.CONCLUSIONS:
Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response.FUNDING:
This research was funded by Roche Pharma Research and Early Development.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Microambiente Tumoral
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Inibidores de Checkpoint Imunológico
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Melanoma
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article