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Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

ABSTRACT: Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

PROVIDER: PRJNA1119430 | ENA |

REPOSITORIES: ENA

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Project description:The differentiation and effector function of tumor infiltrating lymphocytes and macrophages in the tumor microenvironment is critical for productive anti-tumor immune responses, although direct evidence for this remains poorly characterized in brain cancer patients. Using mass cytometry, single-cell RNA sequencing, and quantitative multiplex immunofluorescence, we comprehensively characterized the phenotype and single-cell transcriptome of myeloid cells and T lymphocytes that infiltrated malignant gliomas, and identified how such populations changed following neoadjuvant PD-1 checkpoint blockade in recurrent glioblastoma patients. Cells of the myelo-monocytic lineage represented approximately three quarters of the immune cell infiltrate, with T lymphocytes representing the next major immune cell subset by density and percentage, but following neoadjuvant PD-1 antibody blockade, the ratio of myeloid cells to T cells significantly decreased. We then used single-cell RNA sequencing to comprehensively define the transcriptional profiles of lymphoid and myeloid populations in these tumors. Recurrent GBM patients treated with neoadjuvant PD-1 checkpoint inhibition possessed a greater fraction of CD8+ T cells with an effector T cell transcriptional program. The increased effector T cell populations were associated with the distinct upregulation of the chemokines, CXCL9 and CXCL10 by an interferon-responsive macrophage cluster. Importantly, we also identified that neoadjuvant PD-1 blockade was associated with significantly increased cellular interactions specifically between CD8+ T cells and tumor associated macrophages within the tumor microenvironment. Together, these findings suggest that effector T cell infiltration and differentiation are increased with neoadjuvant PD-1 blockade but impeded by adaptive resistance and immunosuppression from tumor associated macrophages. Future therapeutic strategies to target this dominant immunosuppressive myeloid cell population may be needed to achieve true, therapeutic interventions in this patient population.

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Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study

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