6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice
6Thioguanineloaded polymeric micelles deplete myeloidderived suppressor cells and enhance the efficacy of T cell immunotherapy in tumorbearing mice
Laura Jeanbart 1 2 3
Iraklis C. Kourtis 1 2 3
Andr J. van der Vlies 1 2 3
Melody A. Swartz 0 1 2 3 4
Jeffrey A. Hubbell 0 1 2 3 4
0 Institute for Chemical Sciences and Engineering, School of Basic Sciences, EPFL , Lausanne , Switzerland
1 Materials Science Division, Argonne National Laboratory , Argonne, IL , USA
2 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL , Lausanne , Switzerland
3 Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Federale de Lausanne (EPFL) , Lausanne , Switzerland
4 Institute for Molecular Engineering, University of Chicago , Chicago, IL , USA
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6chi Ly6g monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 days post-injection in tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6clo Ly6g+ granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs,
T cell therapy
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as well as of Ly6chi macrophages, for up to 7 days
following a single administration. MDSC depletion was dose
dependent and more effective with MC-TG than with equal
doses of free TG. Finally, we tested whether this
MDSCdepleting strategy might enhance cancer immunotherapies
in the B16-F10 melanoma model. We found that MC-TG
significantly improved the efficacy of adoptively
transferred, OVA-specific CD8+ T cells in melanoma cells
expressing OVA. These findings highlight the capacity of
MC-TG in depleting MDSCs in the tumor
microenvironment and show promise in promoting anti-tumor immunity
when used in combination with T cell immunotherapies.
MDSC depletion 6-Thioguanine Cancer
Bone marrow
Dendritic cell
Granulocytic
Over the past decades, many novel cancer
immunotherapies have been developed to boost anti-tumor immunity,
targeting a variety of mechanisms including tumor
antigen presentation by dendritic cells (DCs), anti-tumor T
cell priming, overall T cell activation status, immune
suppression, and T cell infiltration in the tumor [1, 2].
Strategies have included cell-based therapies such as transfer
of ex vivo activated DCs or engineered T cells as well as
antibody-based therapies that target specific T cell
inhibitory pathways including CTLA-4 or PD-1/PD-L1 [36].
Despite these efforts, many therapeutic modalities
encounter limited success because of tumor-induced immune
suppression and evasion mechanisms [69]. It has been shown
that targeting these immune suppressive mechanisms
can lead to enhanced immunotherapy efficacy in cancer
[1014].
Myeloid-derived suppressor cells (MDSCs) are a
heterogeneous population of immature myeloid cells,
characterized by their expression of CD11b and Gr1 and lack of
MHCII; they comprise a Ly6chi Ly6g Gr1int monocytic
subset (Mo-MDSCs) and a Ly6clo Ly6g+ Gr1hi
granulocytic subset (G-MDSCs) [15]. MDSCs are induced by
tumor-mediated inflammation [1618], recruited to the
circulation via tumor-derived factors such as IL-1, IL-6,
GM-CSF, G-CSF, and VEGF [1921], and accumulate in
the tumor, tumor-draining lymph node (LN), and spleen,
with MDSC numbers increasing with tumor load [16, 21].
MDSCs play a major role in anti-tumor immunity by
inhibiting both CD8+ and CD4+ T cell activation, proliferation,
and homing [16, 17, 22, 23]. G-MDSCs infiltrate and exert
their suppressive activity in an antigen-specific manner in
the LNs, while Mo-MDSCs, considered as the more
suppressive ones, infiltrate and suppress T cell responses in the
spleen and tumor [18, 2426].
1 3
Strategies to target MDSCs, and thereby improve local T
cell function, include depletion (affecting both recruitment
and expansion in the tumor), functional inhibition, and
differentiation into mature antigen-presenting cells [27, 28].
Ly6chi monocytes and Mo-MDSCs traffic from the bone
marrow (BM) to sites of inflammation via CCR2-signaling
[29], and therapeutic strategies based on CCR2-siRNA
showed significant reduction in inflammatory monocyte
effects in murine models of atherosclerosis, cancer, and
diabetes [30]. Also, all-trans-retinoic acid (RA), which is
important for hematopoietic (...truncated)