TY - JOUR
T1 - Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs
AU - Cresswell, Gregory M.
AU - Wang, Bingbing
AU - Kischuk, Erin M.
AU - Broman, Meaghan M.
AU - Alfar, Rami A.
AU - Vickman, Renee E.
AU - Dimitrov, Dimiter S.
AU - Kularatne, Sumith A.
AU - Sundaram, Chandru P.
AU - Singhal, Sunil
AU - Eruslanov, Evgeniy B.
AU - Crist, Scott A.
AU - Elzey, Bennett D.
AU - Ratliff, Timothy L.
AU - Low, Philip S.
N1 - Funding Information:
We would like to thank the Purdue University Flow Cytometry and Cell Separation Facility, NIH grant P30 CA023168, and the NIH Shared Instrumentation grant S10DO20029 for carrying out live cell sorting and coordinating use of instrumentation, Dr. L. Tiffany Lyle and Victor A. Bernal-Crespo of the Purdue University Histology Research Laboratory for processing, sectioning, and staining of all IHC samples, Veronika Slivova and Alexandra Gol-Chambers of the Indiana University Health Biorepository for collection of human tissue specimens from the IU Health Methodist Hospital (Indianapolis, IN), On Target Laboratories for providing OTL38 compound, and Endocyte for providing folate-conjugated drug compounds, FA-TLR7a and FA-PI3Ki. This work was supported by Endocyte (40001138 to P.S. Low), Purdue University Center for Cancer Research (to T.L. Ratliff), and RO1 DK084454 (to T.L. Ratliff).
Publisher Copyright:
©2020 American Association for Cancer Research.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRb) within the TME and its restriction to the TME. This FRbþ subpopulation could be selectively targeted with folate-linked drugs. Delivery of a folate-targeted TLR7 agonist to these cells (i) reduced their immunosuppressive function, (ii) increased CD8þ T-cell infiltration, (iii) enhanced M1/M2 macrophage ratios, (iv) inhibited tumor growth, (v) blocked tumor metastasis, and (vi) improved overall survival without demonstrable toxicity. These data reveal a broadly applicable strategy across tumor types for reprogramming MDSCs and TAMs into antitumorigenic immune cells using a drug that would otherwise be too toxic to administer systemically. The data also establish FRb as the first marker that distinguishes immunosuppressive from nonimmunosuppressive subsets of MDSCs and TAMs. Because all solid tumors accumulate MDSCs and TAMs, a general strategy to both identify and reprogram these cells should be broadly applied in the characterization and treatment of multiple tumors. Significance: FRb serves as both a means to identify and target MDSCs and TAMs within the tumor, allowing for delivery of immunomodulatory compounds to tumor myeloid cells in a variety of cancers.
AB - Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRb) within the TME and its restriction to the TME. This FRbþ subpopulation could be selectively targeted with folate-linked drugs. Delivery of a folate-targeted TLR7 agonist to these cells (i) reduced their immunosuppressive function, (ii) increased CD8þ T-cell infiltration, (iii) enhanced M1/M2 macrophage ratios, (iv) inhibited tumor growth, (v) blocked tumor metastasis, and (vi) improved overall survival without demonstrable toxicity. These data reveal a broadly applicable strategy across tumor types for reprogramming MDSCs and TAMs into antitumorigenic immune cells using a drug that would otherwise be too toxic to administer systemically. The data also establish FRb as the first marker that distinguishes immunosuppressive from nonimmunosuppressive subsets of MDSCs and TAMs. Because all solid tumors accumulate MDSCs and TAMs, a general strategy to both identify and reprogram these cells should be broadly applied in the characterization and treatment of multiple tumors. Significance: FRb serves as both a means to identify and target MDSCs and TAMs within the tumor, allowing for delivery of immunomodulatory compounds to tumor myeloid cells in a variety of cancers.
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U2 - 10.1158/0008-5472.CAN-20-1414
DO - 10.1158/0008-5472.CAN-20-1414
M3 - Article
C2 - 33203700
AN - SCOPUS:85100400168
VL - 81
SP - 671
EP - 684
JO - Cancer research
JF - Cancer research
SN - 0008-5472
IS - 3
ER -