IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer
| Autor: | Purushottam Lamichhane, Martin J. Cannon, Lavakumar Karyampudi, Deborah Bahr, Keith L. Knutson, Barath Shreeder, Joshua Daum, Ellen L. Goode, Matthew S. Block, Kimberly R. Kalli, James Krempski |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
STAT3 Transcription Factor Cancer Research Myeloid medicine.medical_treatment T-Lymphocytes Programmed Cell Death 1 Receptor Article 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Blocking antibody medicine Tumor Microenvironment Animals Humans RNA Small Interfering B cell Ovarian Neoplasms Tumor microenvironment B-Lymphocytes business.industry Immunosuppression Dendritic Cells medicine.disease Blockade Interleukin-10 Mice Inbred C57BL Interleukin 10 030104 developmental biology medicine.anatomical_structure Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology Cancer research Female RNA Interference Ovarian cancer business |
| Zdroj: | Cancer research. 77(23) |
| ISSN: | 1538-7445 |
| Popis: | Ligation of programmed cell death-1 (PD-1) in the tumor microenvironment is known to inhibit effective adaptive antitumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow–derived dendritic cells (DC) with IL10 led to increased PD-1 expression. Both groups of DCs also responded to PD-1 blockade by increasing production of IL10. Similarly, treatment of ovarian tumor–bearing mice with PD-1 blocking antibody resulted in an increase in IL10 levels in both serum and ascites. While PD-1 blockade or IL10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented antitumor T- and B-cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti–PD-1 (or anti–PD-L1) monotherapies and prompt further studies aimed at identifying such resistance mechanisms. Cancer Res; 77(23); 6667–78. ©2017 AACR. |
| Databáze: | OpenAIRE |
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