Oncotarget

Research Papers:

Targeting myeloid cells in the tumor microenvironment enhances vaccine efficacy in murine epithelial ovarian cancer

Anm Nazmul H. Khan, Nonna Kolomeyevskaya, Kelly L. Singel, Melissa J. Grimm, Kirsten B. Moysich, Sayeema Daudi, Kassondra S. Grzankowski, Sashikant Lele, Lourdes Ylagan, Gill A. Webster, Scott I. Abrams, Kunle Odunsi and Brahm H. Segal _

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Oncotarget. 2015; 6:11310-11326. https://doi.org/10.18632/oncotarget.3597

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Abstract

Anm Nazmul H. Khan1,*, Nonna Kolomeyevskaya2,*, Kelly L. Singel3,*, Melissa J. Grimm1, Kirsten B. Moysich4, Sayeema Daudi2, Kassondra S. Grzankowski2, Sashikant Lele2, Lourdes Ylagan5, Gill A. Webster6, Scott I. Abrams3, Kunle Odunsi2,3 and Brahm H. Segal1,3,7

1 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

2 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA

3 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

4 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA

5 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA

6 Innate Immunotherapeutics, Auckland, New Zealand

7 Department of Medicine, University at Buffalo School of Medicine, Buffalo, NY, USA

* These authors contributed equally to this work

Correspondence to:

Brahm H. Segal, email:

Keywords: ovarian cancer, macrophages, myeloid-derived suppressor cells, vaccination

Received: December 12, 2014 Accepted: February 20, 2015 Published: March 14, 2015

Abstract

Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages, and is associated with a high relapse rate. Patients in remission are ideal candidates for immunotherapy aimed at cure or prolonging disease-free periods. However, immunosuppressive pathways in the tumor microenvironment are obstacles to durable anti-tumor immunity. In a metastatic syngeneic mouse model of EOC, immunosuppressive macrophages and myeloid-derived suppressor cells (MDSCs) accumulate in the local tumor environment. In addition, resident peritoneal macrophages from non-tumor-bearing mice were highly immunosuppressive, abrogating stimulated T cell proliferation in a cell contact-dependent manner. Immunization with microparticles containing TLR9 and NOD-2 ligands (MIS416) significantly prolonged survival in tumor-bearing mice. The strategy of MIS416 immunization followed by anti-CD11b administration further delayed tumor progression, thereby establishing the proof of principle that myeloid depletion can enhance vaccine efficacy. In patients with advanced EOC, ascites analysis showed substantial heterogeneity in the relative proportions of myeloid subsets and their immunosuppressive properties. Together, these findings point to immunosuppressive myeloid cells in the EOC microenvironment as targets to enhance vaccination. Further studies of myeloid cell accumulation and functional phenotypes in the EOC microenvironment may identify patients who are likely to benefit from vaccination combined with approaches that deplete tumor-associated myeloid cells.


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