Clinical MedicineHematologyImmunology Open Access | 10.1172/JCI161109

Andres Chang,1,2 Anton M. Sholukh,3,4 Andreas Wieland,2 David L. Jaye,5 Mary Carrington,6,7 Meei-Li Huang,3,4 Hong Xie,3,4 Keith R. Jerome,3,4 Pavitra Roychoudhury,3,4 Alexander L. Greninger,3,4 Jean L. Koff,1 Jonathon B. Cohen,1 David M. Koelle,3,4,8,9,10 Lawrence Corey,3,4,8 Christopher R. Flowers,1 and Rafi Ahmed2

1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

Find articles by Chang, A. in: JCI | PubMed | Google Scholar |

1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

Find articles by Cohen, J. in: JCI | PubMed | Google Scholar

1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

Find articles by Corey, L. in: JCI | PubMed | Google Scholar |

1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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1Department of Hematology and Medical Oncology, Winship Cancer Institute and

2Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine Atlanta, Georgia, USA.

3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

4Departments of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

5Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

6Basic Science Program, Frederick National Laboratory for Cancer Research, and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

7Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.

8Department Medicine and

9Department of Global Health, University of Washington, Seattle, Washington, USA.

10Department of Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA.

Address correspondence to: Christopher R. Flowers, Chair, Professor, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429 Houston, Texas 77030, USA. Phone: 713.745.6095; Email: crflowers@mdanderson.org. Or to: Rafi Ahmed, Director, Emory Vaccine Center, Georgia Research Alliance Eminent Scholar, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Phone: 404.727.4700; Email: rahmed@emory.edu. AW’s present address is: Department of Otolaryngology and Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio, USA.

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Published July 21, 2022 - More info

Published in Volume 132, Issue 18 on September 15, 2022
J Clin Invest. 2022;132(18):e161109. https://doi.org/10.1172/JCI161109.
© 2022 Chang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published July 21, 2022 - Version history
Received: April 15, 2022; Accepted: July 19, 2022 View PDF Abstract

Background. Herpes simplex virus lymphadenitis (HSVL) is an unusual presentation of HSV reactivation in patients with chronic lymphocytic leukemia (CLL) and is characterized by systemic symptoms and no herpetic lesions. The immune responses during HSVL have not, to our knowledge, been studied.

Methods. Peripheral blood and lymph node (LN) samples were obtained from a patient with HSVL. HSV-2 viral load, antibody levels, B and T cell responses, cytokine levels, and tumor burden were measured.

Results. The patient showed HSV-2 viremia for at least 6 weeks. During this period, she had a robust HSV-specific antibody response with neutralizing and antibody-dependent cellular phagocytotic activity. Activated (HLA-DR+, CD38+) CD4+ and CD8+ T cells increased 18-fold, and HSV-specific CD8+ T cells in the blood were detected at higher numbers. HSV-specific B and T cell responses were also detected in the LN. Markedly elevated levels of proinflammatory cytokines in the blood were also observed. Surprisingly, a sustained decrease in CLL tumor burden without CLL-directed therapy was observed with this and also a prior episode of HSVL.

Conclusion. HSVL should be considered part of the differential diagnosis in patients with CLL who present with signs and symptoms of aggressive lymphoma transformation. An interesting finding was the sustained tumor control after 2 episodes of HSVL in this patient. A possible explanation for the reduction in tumor burden may be that the HSV-specific response served as an adjuvant for the activation of tumor-specific or bystander T cells. Studies in additional patients with CLL are needed to confirm and extend these findings.

Funding. NIH grants 4T32CA160040, UL1TR002378, and 5U19AI057266 and NIH contracts 75N93019C00063 and HHSN261200800001E. Neil W. and William S. Elkin Fellowship (Winship Cancer Institute).

Introduction

Herpes simplex virus 2 (HSV-2) is a sexually transmitted infection that establishes a chronic latent infection in the associated dorsal root ganglion, with episodes of reactivation and viral shedding that are asymptomatic or result in typical, localized herpetic lesions (1, 2). However, in patients with chronic lymphocytic leukemia (CLL), HSV reactivation may not lead to the development of herpetic lesions but instead can result in HSV lymphadenitis (HSVL). Patients with HSVL usually present with fever, night sweats, and worsening lymphadenopathy (3). Because of these signs and symptoms and the absent herpetic lesions, HSVL is often mistaken as aggressive lymphoma transformation. The pathophysiology of this unusual and challenging diagnosis is unknown but is not associated with CLL subtype or therapy (4). It is hypothesized that immunological defects caused by CLL contribute to this manifestation, but, to our knowledge, the immune responses in HSVL have not been examined. Here, we present a detailed analysis of the HSV-specific adaptive immune responses in a patient with CLL who had recurrent HSVL, and we report the concomitant presence of viremia caused by a typical HSV-2 strain and describe a sustained decrease in tumor burden after each occurrence.

Patient case description. A 79-year-old woman with treatment-naive CLL (del13q and trisomy 12) presented approximately 7 years after diagnosis with a 5-day history of fatigue, malaise, and tender, rapidly enlarging left inguinal adenopathy but no mucocutaneous lesions. Laboratory testing revealed new-onset anemia and thrombocytopenia but normal lactate dehydrogenase (LDH). A bone marrow biopsy showed CLL involvement with no evidence of aggressive lymphoma. Fluorodeoxyglucose PET/CT (FDG-PET/CT) showed retroperitoneal and left iliac adenopathy and a left groin mass measuring 7.4 × 4.3 cm with a maximum standardized uptake value (SUV) of 14.3 (Figure 1A). Excisional biopsy of the mass 17 days after symptom onset revealed a lymph node (LN) involved by CLL with prominent necrotic areas but no aggressive lymphoma (Figure 1B). Prior reports indicated that HSV reactivation in patients with CLL can, in rare instances, cause these symptoms (4). Thus, to confirm this diagnosis, we performed immunohistochemical staining for HSV-1/-2, which showed HSV-infected cells (Figure 1C). PCR of LN material was also positive for HSV-2. The patient was treated with corticosteroids and valacyclovir followed by acyclovir prophylaxis, with complete symptom resolution and no recurrence for over 3 years.

Figure 1

Clinical presentation of HSVL in a patient with CLL. (A) A PET/CT scan obtained at presentation showed left-sided FDG-avid adenopathy. (B) Low- and high-power micrographs of H&E staining showing areas of necrosis (arrow) in the biopsy specimen of the FDG-avid left obturator node. Original magnification, ×40 (left) and ×600 (right). (C) Cells stained for HSV-1/-2 major capsid protein were found in the biopsy sample (brown). Original magnification, ×200 (left) and ×400 (right). (D) Plasma HSV-2 genome copies over time showing evidence of HSV-2 viremia. Vertical dotted line indicates the time of presentation; arrow indicates the time of antiviral therapy initiation. (E) Top: Sequence coverage depth for plasma-derived HSV-2 DNA from day +5 (green) and day +12 (purple). Coordinates are from the HSV-2 reference strain HG52 (GenBank accession JN561323.2). Poor coverage of UL and US inverted repeats is commonly noted with short-read technologies. Bottom: Schematic of HSV-2 genomes showing inverted repeats and HSV-1 insertions in 3 indicated HSV ORFs that are prevalent in North American strains (5) and that were detected in both patient specimens.

Results

HSV-2 viremia and viral sequence. The availability of baseline and longitudinal samples collected within 270 days of presentation (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI161109DS1) allowed us to study the virology of and immunological responses in HSVL. Plasma real-time quantitative PCR revealed HSV-2 viremia, with detectable viral DNA for at least 6 weeks (Figure 1D). High-resolution sequencing recovered more than 99% of known protein-coding regions of the HSV-2 genome from the blood on days +5 and +12, which showed no significant differences between samples, displayed high similarities to common US strains, and showed no genotypic evidence of acyclovir resistance (Figure 1E) (5, 6). These findings indicate that reactivation of a conventional HSV-2 strain, and not a distinct HSV-2 variant, produced a systemic infection in this patient.

HSV-specific antibody responses in HSVL. Patients with CLL are known to have a dysregulated immune system (7), but the immunological factors that allowed for this patient’s clinical presentation were unknown. Thus, we set out to further evaluate the HSV-specific adaptive immune responses in our patient. Flow cytometric analysis (FACS) of PBMCs detected higher numbers of antibody-secreting cells (plasmablasts), defined as CD19+CD3–CD20–/loCD38hiIgD– lymphocytes, at presentation compared with other time points (Figure 2A) (8). Plasmablasts lacked CD5 expression, indicating that these were not CLL cells. Assessment of the LN sample obtained on day +17 also showed high numbers of plasmablasts by FACS (Figure 2B, left). Using an ELISPOT assay, we confirmed that plasmablasts in the LN secreted IgG antibodies that recognized HSV-2 (Figure 2B, right) (8).

Figure 2

Vigorous HSV-specific B cell responses were observed in the blood and LN. (A) Quantification of plasmablasts per million live PBMCs in the blood over time. Red indicates the viral titer depicted in Figure 1C. (B) Flow cytometric analysis shows plasmablasts in the LN (left). ELISPOT assay (right) shows that LN plasmablasts secreted HSV-2–specific IgG antibodies. (C) Persistent hypogammaglobulinemia was observed in this patient. Shaded area indicates the expected normal range. (D) Relative IgG-binding titers against HSV-2 lysates by ELISA (blue) and neutralizing antibody titers leading to a 50% reduction in virus infectivity (black). Error bars indicate the SEM. Positive control neutralizing antibody titer = 1:256. (E) IgG, IgA, and IgM antibody binding to different HSV-2 surface proteins at each time point versus pooled plasma from HSV-2+ and HSV-1/-2– controls. White denotes the sample not analyzed. (F) HSV-2 ADCP score (in thousands) of gD2-covered microspheres incubated with plasma from each time point. ADCP score for pooled healthy HSV-2+ control = 111,320. Error bars indicate the SD. (G) IgG subclass analysis of antibodies that bound to HSV-2 surface proteins at each time point versus pooled plasma from HSV-2+ and HSV-1/-2– controls. For E and G, antibody binding to influenza HA (FluHA) was included as a control. Heatmap scale reflects the endpoint titer in log2. All measurements were performed in duplicate. For all applicable graphs, the vertical dotted line indicates the time of presentation. Day, days since symptom onset.

Despite the patient’s persistent hypogammaglobulinemia (Figure 2C), as is often seen in CLL, HSV-2–specific IgG titers were detectable at baseline, started to increase by day 12, and peaked after 6 weeks, resulting in a 14-fold increase (P = 0.0015, Figure 2D). These antibodies reacted against the 4 major HSV-2 glycoproteins (gB2, gC2, gD2, and the gH2/gL2 heterodimer) and remained elevated for at least 270 days (Figure 2E). Increases in HSV-2–specific IgA titers were similar to those of IgG, whereas IgM titers only increased 1- to 2-fold (Figure 2E).

To determine the functional capacity of these antibodies, we measured their neutralizing potential and their capacity to elicit antibody-dependent cellular phagocytosis (ADCP). Neutralizing antibody titers increased 13.5-fold by week 6 (Figure 2D). ADCP capacity against gD2-covered microspheres also increased, peaking at 90 days (Figure 2F). We also measured IgG subclasses of the HSV-2–specific antibodies and found a predominant IgG1 response (Figure 2G), consistent with ADCP and neutralizing activity. We also observed significant IgG2 and IgG3 responses. IgG1 and IgG3 antibodies have potent Fc effector functions and usually increase in response to viral infections (9). We also detected changes