Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches
Abstract
:1. Introduction
2. Differentiation, Characteristics, and Mechanisms of MDSCs Function
3. Preclinical Studies Delineating the Significance of MDSCs in Pancreatic Cancer and Therapies
3.1. Genetically Engineered Mouse Models of Pancreatic Cancer in MDSCs Studies
3.2. Immune Mediators Affecting MDSCs Function, and Approaches Targeting MDSCs in Mice Models Including GEMM
4. Clinical Studies Delineating the Role of MDSCs in Pancreatic Cancer and Therapies
4.1. Characterization of MDSCs in PDAC Patients
4.2. Effects of Therapeutic Agents on MDSCs Levels in PDAC Patients
5. Conclusions
Funding
Conflicts of Interest
References
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MDSCs | Common PMN-MDSCs Markers | Common M-MDSCs Markers | eMDSCs |
---|---|---|---|
Human | HLA-DR-CD33+CD11b+CD15+CD14− | HLA-DRlow-CD11b+ CD14+ CD15− | Lin−(CD3/14/15/19/56)/HLA-DR−/CD33+ |
Murine | CD11b+Gr-1+Ly6GhighLy6Clow | CD11b+Gr-1+Ly6GlowLy6Chigh | — |
Mouse Models | Cells Lines | Therapeutic Agent(s) | Findings | Target(s) | Ref. |
---|---|---|---|---|---|
CD11b-DTR, iKras*, iKras*P53*, iKras*; CD11b-DTR, iKras*; p53*; CD11b-DTR mice | Primary human (1319, UM2, UM5, UM18 and UM19) and primary mouse (iKras*1, iKRAS*2, iKras*3, 65 671, 7940B) cell lines | – | Myeloid cell subsets favor tumor immunoevasion in EGFR-MAPK-dependent regulation of tumoral PD-L1 expression and inhibition of CD8+ T cell antitumor immunity | KrasG12D, PD-L1 | [19] |
KrasLSL-G12D/+; Cre (KC) and KrasLSL-G12D/+; Trp53LSL-R172H/+; Cre (KPC) mice | – | – | G-MDSCs inhibit T cell proliferation and induce T cell death and its depletion unmask PDAC to adaptive immune response. | – | [24] |
EL-TGF-α/p53−/− double transgenic, EL-TGF-α/p53+/− heterozygous, C57BL/6 and BALB/c mice | Murine mPAC cell line | – | Increased frequency of MDSCs was detected at early stages of tumor development with further increased during tumor progression. | – | [39] |
KCR, KC, RAGE-null, and C57BL/6- wild type mice | – | – | RAGE ablation resulted in the accumulation of MDSCs. | RAGE | [40] |
GCSFR−/−, NU/J and C57BL/6-WT mice | KCM, KCKO, Panc-1, BxPC3 and Pan02 cell lines | – | STAT3 signaling in M-MDSCs promotes CSCs stemness in pancreatic cancer. | STAT3 | [41] |
C57BL/6 mice | Murine Panc02 cell line | Sildenafil | Sildenafil treatment reduced MDSCs frequency and VEGF levels and increased the survival of tumor-bearing female mice. | VEGF | [42] |
NOD/SCID mice | PANC-1, CFPAC-1 and EL4 cell lines | Neutralizing antibodies against PAUF and TLR4, and inhibitor of the MAPK pathway | PAUF regulates the functional activation of MDSCs via TLR4 and the MAPK-dependent pathways. | PAUF | [43] |
TLR4−/− C57BL/6-WT and Nude mice | EL4, MSC-1 and MSC-2 cell lines | Cyclophosphamide, doxorubicin, oxaliplatin, paclitaxel, gemcitabine, 5FU, and raltitrexed | 5FU-mediated depletion of MDSCs promoted CD8+T-cell-dependent anti-tumor responses. | – | [44] |
Severe combined immunodeficiency disease (SCID) and C57BL/6-WT mice | Human Panc-1 and Murine Panc-02 cell lines | Gemcitabine, metronomic chemotherapy (MC) with gemcitabine and anti-Bv8 antibody | MC with gemcitabine or anti-Bv8 antibody enhanced gemcitabine efficacy. | – | [45] |
LSL-KrasG12D; Pdx-1/Cre (KC) and pdx-1/Cre (Cre) mice | Murine PDA cell line | Monoclonal antibody targeting ENO1 | Anti-ENO1 impaired MDSCs invasion and elicited sustained effector T-cell function. | ENO1 | [46] |
KPC Cxcr2−/− and KPC mice | – | CXCR2 inhibitor, gemcitabine, and anti-PD1 immunotherapy | CXCR2 inhibition suppressed metastasis and enhanced therapeutic responses of chemotherapy and immunotherapy to prolong mice survival. | CXCR2 | [47] |
NOD/SCID mice | Human Hs766t, and MIA PaCa-2 cell lines | Serp-1, neuroserpin, and M-T7 | Serp-1 and neuroserpin treatment reduced pancreatic tumor growth via decreasing splenic and tumoral MDSCs as well as tumor infiltration of macrophage. | uPA | [48] |
Therapeutic Agent(s) | Findings | Ref. |
---|---|---|
– | MDSCs play an essential role in pancreatic cancer but were not correlated with tumor stage. | [15] |
– | MDSCs play importance role in pancreatic cancer progression | [66] |
– | M-MDSCs can be characterized as circulating STAT3/arginase-1-expressing CD14+ cells in pancreatic cancer patients. | [67] |
Chemotherapy + Cytokine-induced killer cell (CIK) immunotherapy | MDSCs-targeting chemotherapy improved the survival response of CIK immunotherapy. | [14] |
Chemotherapy | Analysis of MDSCs in peripheral blood may represent a predictive biomarker for chemotherapy failure in pancreatic cancer patients. | [30] |
Zoledronic Acid (ZA) | No differences were observed in the prevalence of G-MDSCs in the blood and bone marrow of PDAC patients treated (pre- and post) with ZA. | [68] |
Gemcitabine + Capecitabine alone versus GV1001 vaccine with gemcitabine + capecitabine along with GM-CSF as adjuvant | Gemcitabine and capecitabine combination did not result in a consistent reduction in MDSCs levels. High levels of MDSCs pre-vaccination do not prevent the development of an immune response to tumor antigens. | [69] |
CDDO-Me alone and CDDO-Me combination with gemcitabine | CDDO-Me abrogated the immune suppressive effects of MDSCs and improved immune response. | [70] |
DS-82373a, an agonistic TRAIL-R2 antibody | DS-82373a selectively reduced MDSCs subsets in peripheral blood and tumor tissues of cancer patients, including pancreatic cancer. | [71] |
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Thyagarajan, A.; Alshehri, M.S.A.; Miller, K.L.R.; Sherwin, C.M.; Travers, J.B.; Sahu, R.P. Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches. Cancers 2019, 11, 1627. https://doi.org/10.3390/cancers11111627
Thyagarajan A, Alshehri MSA, Miller KLR, Sherwin CM, Travers JB, Sahu RP. Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches. Cancers. 2019; 11(11):1627. https://doi.org/10.3390/cancers11111627
Chicago/Turabian StyleThyagarajan, Anita, Mamdouh Salman A. Alshehri, Kelly L.R. Miller, Catherine M. Sherwin, Jeffrey B. Travers, and Ravi P. Sahu. 2019. "Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches" Cancers 11, no. 11: 1627. https://doi.org/10.3390/cancers11111627