IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer

Purushottam Lamichhane, Lavakumar Karyampudi, Barath Shreeder, James Krempski, Deborah Bahr, Joshua Daum, Kimberly R. Kalli, Ellen L Goode, Matthew S Block, Martin J. Cannon, Keith L Knutson

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6667-6678
Number of pages12
JournalCancer Research
Volume77
Issue number23
DOIs
StatePublished - Dec 1 2017

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Interleukin-10
Ovarian Neoplasms
Immunosuppression
Cell Death
Dendritic Cells
Neoplasms
Blocking Antibodies
Tumor Microenvironment
Adaptive Immunity
Myeloid Cells
Immunosuppressive Agents
Ascites
Ligation
B-Lymphocytes
Bone and Bones
Survival
Therapeutics
Growth
Serum

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lamichhane, P., Karyampudi, L., Shreeder, B., Krempski, J., Bahr, D., Daum, J., ... Knutson, K. L. (2017). IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer. Cancer Research, 77(23), 6667-6678. https://doi.org/10.1158/0008-5472.CAN-17-0740

IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer. / Lamichhane, Purushottam; Karyampudi, Lavakumar; Shreeder, Barath; Krempski, James; Bahr, Deborah; Daum, Joshua; Kalli, Kimberly R.; Goode, Ellen L; Block, Matthew S; Cannon, Martin J.; Knutson, Keith L.

In: Cancer Research, Vol. 77, No. 23, 01.12.2017, p. 6667-6678.

Research output: Contribution to journalArticle

Lamichhane, P, Karyampudi, L, Shreeder, B, Krempski, J, Bahr, D, Daum, J, Kalli, KR, Goode, EL, Block, MS, Cannon, MJ & Knutson, KL 2017, 'IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer', Cancer Research, vol. 77, no. 23, pp. 6667-6678. https://doi.org/10.1158/0008-5472.CAN-17-0740
Lamichhane P, Karyampudi L, Shreeder B, Krempski J, Bahr D, Daum J et al. IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer. Cancer Research. 2017 Dec 1;77(23):6667-6678. https://doi.org/10.1158/0008-5472.CAN-17-0740
Lamichhane, Purushottam ; Karyampudi, Lavakumar ; Shreeder, Barath ; Krempski, James ; Bahr, Deborah ; Daum, Joshua ; Kalli, Kimberly R. ; Goode, Ellen L ; Block, Matthew S ; Cannon, Martin J. ; Knutson, Keith L. / IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer. In: Cancer Research. 2017 ; Vol. 77, No. 23. pp. 6667-6678.
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