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Poster Sessions| November 16, 2005

Hsp90 Is Critical for the Regulation of Human T Lymphocytes and NK Cell Phenotype and Function.

Jooeun Bae, PhD,

Jooeun Bae, PhD

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Constantine Mitsiades, M.D.,

Constantine Mitsiades, M.D.

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Rao Prabhala Prabhala, PhD,

Rao Prabhala Prabhala, PhD

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Tai Yu-Tzu, PhD,

Tai Yu-Tzu, PhD

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Jeff Martinson, BS,

Jeff Martinson, BS *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Steven Hartson, PhD,

Steven Hartson, PhD *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Teru Hideshima, PhD,

Teru Hideshima, PhD

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Lawrence Catley, M.D.,

Lawrence Catley, M.D. *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Xianfeng Li, BS,

Xianfeng Li, BS *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Ramesh Babu Batchu, PhD,

Ramesh Babu Batchu, PhD *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Robert Bertheau, BS,

Robert Bertheau, BS *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Shammas Masood, PhD,

Shammas Masood, PhD *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Sushima Samala, M.S.,

Sushima Samala, M.S. *

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Jeff Miller, PhD,

Jeff Miller, PhD

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Kenneth Anderson, M.D.,

Kenneth Anderson, M.D.

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Nikhil Munshi, M.D.

Nikhil Munshi, M.D.

¹Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; ²Immunology, Rush University Medical Center, Chicago, IL, USA; ³Biochemistry and Molecular Biology, Oklahoma State Univeristy, Stillwater, OK, USA and ⁴Medical and Pediatric Hematology-Oncology, University of Minnesota Cancer Center, Minneapolis, MN, USA.

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Blood (2005) 106 (11): 3464.

https://doi.org/10.1182/blood.V106.11.3464.3464

Abstract

Hsp90 inhibitor has shown promising anti-tumor activity through the destabilization and eventual degradation of Hsp90 client proteins critical for cell survival. In this study, we examined the in vitro effects of Hsp90 inhibitor on the phenotype and function of human T lymphocytes and NK cells. We observed no significant effects of Hsp90 inhibitor treatment on cell survivals. However, Hsp90 inhibitor treatment for 24 hours led to irreversible down-regulation of expression of critical T-cell surface antigens including CD3, CD4, CD8, CD28, CD154 (CD40L) and TCRab. Among the antigens evaluated, expression of CD4 antigen was most significantly downregulated (untrt vs. trt = 326 vs. 88 in Mean Fluorescence Intensity) following Hsp90 inhibitor treatment. Decreased CD3⁺ T lymphocytes proliferation (untrt vs. trt = 222839 cpm vs. 111102 cpm, ³[H]-thymidine incorporation) and reduced IFN-g secretion (untrt vs. trt = 77 vs. 48 pg/ml) was observed upon stimulation with allogeneic dendritic cells following 24 hrs treatments of T cells with Hsp90 inhibitor. Furthermore, CD3⁺ T-cell proliferation in response to mitogen stimulation, as measured by flow cytometry using CFSE was decreased following Hsp90 inhibitor treatment (untrt vs. trt = 41% vs. 3%, CFSE). Specifically, the CD4⁺CD28⁺ (untrt vs. trt = 32% vs. 1%) and CD8⁺CD28⁺ (untrt vs. trt = 27% vs. 17%) activated T-cell subpopulations displayed a significant decrease in proliferation in response to mitogen. Similarly, NK cells displayed decreased activation receptor expression including CD2, CD11a, CD94, NKp30, NKp44, NKp46, and KARp50.3 and reduced cytotoxic activity against multiple myeloma cells (untrt vs. trt = 49% vs. 11% against MM1S cells, 65% vs. 8% against ARP cells) following Hsp90 inhibitor treatment. These studies demonstrate that Hsp90 inhibitor treatment significantly affects phenotype and function of human T-lymphocytes as well as NK cells, and suggest the need to monitor immune functions in patients being treated with Hsp90 inhibitor in our future studies.

Author notes

Corresponding author

2005, The American Society of Hematology

2005

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