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Cancer Immunol Res. 2016 Jun;4(6):531-40. doi: 10.1158/2326-6066.CIR-15-0250. Epub 2016 Apr 4.

Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 and PD-1 Antibodies in Melanoma.

Author information

1
Department of Preclinical Research, Peregrine Pharmaceuticals, Inc., Tustin, California.
2
Hamon Center for Therapeutic Oncology Research, Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas.
3
Department of Molecular Biology and Biochemistry, University of California, Irvine, California.
4
Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
5
Hamon Center for Therapeutic Oncology Research, Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
6
Hamon Center for Therapeutic Oncology Research, Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas. xianming88@yahoo.com.

Abstract

In tumor-bearing animals, the membrane phospholipid phosphatidylserine (PS) suppresses immune responses, suggesting that PS signaling could counteract the antitumor effect of antibody-driven immune checkpoint blockade. Here, we show that treating melanoma-bearing mice with a PS-targeting antibody enhances the antitumor activity of downstream checkpoint inhibition. Combining PS-targeting antibodies with CTLA-4 or PD-1 blockade resulted in significantly greater inhibition of tumor growth than did single-agent therapy. Moreover, combination therapy enhanced CD4(+) and CD8(+) tumor-infiltrating lymphocyte numbers; elevated the fraction of cells expressing the proinflammatory cytokines IL2, IFNγ, and TNFα; and increased the ratio of CD8 T cells to myeloid-derived suppressor cells and regulatory T cells in tumors. Similar changes in immune cell profiles were observed in splenocytes. Taken together, these data show that antibody-mediated PS blockade enhances the antitumor efficacy of immune checkpoint inhibition. Cancer Immunol Res; 4(6); 531-40.

PMID:
27045021
DOI:
10.1158/2326-6066.CIR-15-0250
[Indexed for MEDLINE]
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