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 - Publisher Copyright:
©2020 American Association for Cancer Research.
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 (FRβ) within the TME and its restriction to the TME. This FRβ
+ 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 CD8
+ 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 FRβ 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: FRβ 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 (FRβ) within the TME and its restriction to the TME. This FRβ
+ 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 CD8
+ 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 FRβ 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: FRβ 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.
KW - Adenocarcinoma/pathology
KW - Animals
KW - Biomarkers, Tumor/metabolism
KW - Breast Neoplasms/pathology
KW - CD8-Positive T-Lymphocytes/drug effects
KW - Cell Line, Tumor
KW - Cell Polarity
KW - Cellular Reprogramming Techniques
KW - Cytokines/metabolism
KW - Folate Receptor 2/metabolism
KW - Folic Acid/pharmacology
KW - Humans
KW - Immunomodulation/drug effects
KW - Lung Neoplasms/pathology
KW - Macrophages/cytology
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Myeloid Cells/drug effects
KW - Myeloid-Derived Suppressor Cells/immunology
KW - Tumor Microenvironment/immunology
KW - Tumor-Associated Macrophages/immunology
KW - Up-Regulation
UR - http://www.scopus.com/inward/record.url?scp=85100400168&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100400168&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-1414
DO - 10.1158/0008-5472.CAN-20-1414
M3 - Article
C2 - 33203700
AN - SCOPUS:85100400168
SN - 0008-5472
VL - 81
SP - 671
EP - 684
JO - Cancer research
JF - Cancer research
IS - 3
ER -