High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance.

Autor:	Saeed MA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Peng B; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Kim K; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Rawat K; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Kuehm LM; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Siegel ZR; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Borkowski A; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Habib N; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri., Van Tine B; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri., Sheikh N; Dendreon Pharmaceuticals LLC, Seattle, Washington., Tuyen V; Dendreon Pharmaceuticals LLC, Seattle, Washington., Thorek DLJ; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri., Fehniger TA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.; Bursky Center for Human Immunology and Immunotherapy, Washington University School of Medicine, St Louis, Missouri., Pachynski RK; Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri.; Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.; Bursky Center for Human Immunology and Immunotherapy, Washington University School of Medicine, St Louis, Missouri.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2024 May 02; Vol. 12 (5), pp. 559-574.
DOI:	10.1158/2326-6066.CIR-23-0652
Abstrakt:	Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2- to 14-fold higher influx of sip-T and a significant increase in IFNγ producing CD8+ T cells and NKT cells within the tumor microenvironment in the IL15 group. In conclusion, we put forward evidence that IL15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL15 or IL15 agonists with sip-T to treat patients with mCRPC. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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