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 language | English (US) |
|---|---|
| Pages (from-to) | 6667-6678 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 77 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2017 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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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 journal › Article
}
TY - JOUR
T1 - IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer
AU - Lamichhane, Purushottam
AU - Karyampudi, Lavakumar
AU - Shreeder, Barath
AU - Krempski, James
AU - Bahr, Deborah
AU - Daum, Joshua
AU - Kalli, Kimberly R.
AU - Goode, Ellen L
AU - Block, Matthew S
AU - Cannon, Martin J.
AU - Knutson, Keith L
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85036511821&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85036511821&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-0740
DO - 10.1158/0008-5472.CAN-17-0740
M3 - Article
C2 - 28993412
AN - SCOPUS:85036511821
VL - 77
SP - 6667
EP - 6678
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 23
ER -