Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells.

Autor:	Somasundaram A; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Cillo AR; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Lampenfeld C; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Workman CJ; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Kunning S; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Oliveri L; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Velez M; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Joyce S; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Calderon M; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Dadey R; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Rajasundaram D; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Normolle DP; Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania., Watkins SC; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Herman JG; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Kirkwood JM; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Lipson EJ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland., Ferris RL; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Bruno TC; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania., Vignali DAA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2022 Jul 01; Vol. 10 (7), pp. 885-899.
DOI:	10.1158/2326-6066.CIR-20-0736
Abstrakt:	Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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