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.
N1 - Funding Information:
This work was supported by the Minnesota Ovarian Cancer Alliance (K.L. Knutson and L. Karyampudi), the Fred C. and Katherine B. Andersen Foundation (K.L. Knutson and K.R. Kalli), the Marsha Rivkin Center for Ovarian Cancer Research (L. Karyampudi, K.L. Knutson, and M.J. Cannon), Mayo Clinic Comprehensive Cancer Center grant P30-CA015083 (R. Diasio), and the Mayo Clinic Ovarian Cancer SPORE (P50-CA136393 to K.L. Knutson, E.L. Goode, M. S. Block, and M.J. Cannon).
Funding Information:
M.S. Block reports receiving other commercial research support from Merck. No potential conflicts of interest were disclosed by the other authors. The authors are grateful for the technical support of Laura Lewis-Tuffin and the Mayo Clinic Florida Flow Cytometry and Cell Analysis Shared Resource. This work was supported by the Minnesota Ovarian Cancer Alliance (K.L. Knutson and L. Karyampudi), the Fred C. and Katherine B. Andersen Foundation (K.L. Knutson and K.R. Kalli), the Marsha Rivkin Center for Ovarian Cancer Research (L. Karyampudi, K.L. Knutson, and M.J. Cannon), Mayo Clinic Comprehensive Cancer Center grant P30-CA015083 (R. Diasio), and the Mayo Clinic Ovarian Cancer SPORE (P50-CA136393 to K.L. Knutson, E.L. Goode, M. S. Block, and M.J. Cannon). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
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 - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 23
ER -