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Immunosuppressive CD10+ALPL+ neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells.
- Source :
-
Journal of Hepatology . Dec2023, Vol. 79 Issue 6, p1435-1449. 15p. - Publication Year :
- 2023
-
Abstract
- Remodeling the tumor microenvironment is a critical strategy for treating advanced hepatocellular carcinoma (HCC). Yet, how distinct cell populations in the microenvironment mediate tumor resistance to immunotherapies, such as anti-PD-1, remains poorly understood. We analyzed the transcriptomic profile, at a single-cell resolution, of tumor tissues from patients with HCC scheduled to receive anti-PD-1-based immunotherapy. Our comparative analysis and experimental validation using flow cytometry and histopathological analysis uncovered a discrete subpopulation of cells associated with resistance to anti-PD-1 treatment in patients and a rat model. A TurboID-based proximity labeling approach was deployed to gain mechanistic insights into the reprogramming of the HCC microenvironment. We identified CD10+ALPL+ neutrophils as being associated with resistance to anti-PD-1 treatment. These neutrophils exhibited a strong immunosuppressive activity by inducing an apparent "irreversible" exhaustion of T cells in terms of cell number, frequency, and gene profile. Mechanistically, CD10+ALPL+ neutrophils were induced by tumor cells, i.e. , tumor-secreted NAMPT reprogrammed CD10+ALPL+ neutrophils through NTRK1, maintaining them in an immature state and inhibiting their maturation and activation. Collectively, our results reveal a fundamental mechanism by which CD10+ALPL+ neutrophils contribute to tumor immune escape from durable anti-PD-1 treatment. These data also provide further insights into novel immunotherapy targets and possible synergistic treatment regimens. Herein, we discovered that tumor cells reprogrammed CD10+ALPL+ neutrophils to induce the "irreversible" exhaustion of T cells and hence allow tumors to escape from the intended effects of anti-PD-1 treatment. Our data provided a new theoretical basis for the elucidation of special cell populations and revealed a molecular mechanism underpinning resistance to immunotherapy. Targeting these cells alongside existing immunotherapy could be looked at as a potentially more effective therapeutic approach. [Display omitted] • CD10+ALPL+ neutrophils contribute to tumor resistance to anti-PD-1 treatment in patients with HCC. • CD10+ALPL+ neutrophils exhibit immunosuppressive features in the tumor microenvironment. • CD10+ALPL+ neutrophils trigger irreversible T-cell exhaustion in anti-PD-1-resistant patients. • Hepatoma cell-derived NAMPT-NTRK1 axis reprograms CD10+ALPL+ neutrophils to maintain an immature and immunosuppressive state. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01688278
- Volume :
- 79
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Journal of Hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 173853695
- Full Text :
- https://doi.org/10.1016/j.jhep.2023.08.024