【2】Systemic Administration of Toll-like Receptor 7 (TLR7) Agonist Enhancesthe Efficacy of Immune Checkpoint Inhibitors
RESEARCHERS LED BY TMDU pro-vation of dendritic cells that trigger in-

Miyuki Azuma

posed a new combination immunother-nate immune responses and subsequent-

apy using a TLR7 agonist to improve

ly enhances the ability of killer T cells,

treatment efficacy of immune check-

resulting in the elimination of virally

point inhibitors (ICIs).

infected cells and tumor cells. DespiteDDS, Ph.D., Professor
Department ofMolecular Immunology,Graduate School of
Medical and DentalSciences, TMDU

The release of negative regulators insuch promising effects of resiquimod,

immune activation (immune check-its clinical application has been limitedpoints) that interferes with beneficial

in the usage of topical/local application

demonstrated that limited doses of re-antitumor immune responses brings ato avoid cytokine storms.

siquimod or decreased frequency of thebenefit to cancer patients. CTLA-4 andThe research group examined the anti-

PD-L1 inhibitor could efficiently re-PD-1 are such immune checkpoint mol-tumor effects of the systemic applica-

gress tumor growth. Their results sug-

ecules that negatively regulate T-celltion of low-dose resiquimod in two PD-

gest that limited doses of systemic re-activation. Treatment with humanized

L1 blockade-resistant tumors thatsiquimod administration enableantibodies against CTLA-4 and PD-1

exhibited different profiles of tumor-in-

resistance to PD-1/PD-L1 blockades to(ICIs) have shown to a great achieve-

filtrating lymphocytes (TILs). Resiqui-

be overcome, allowing for the decreased

ment in patients with a variety of can-mod monotherapy markedly inhibited

usage of PD-1/PD-L1 inhibitors.

cers. Now, immunotherapy has been ac-tumor growth in a squamous cell carci-

cepted as the fourth pillar of cancernoma model with abundant infiltration

The article, “Systemic administra-

therapy, following surgery, radiotherapyof regulatory T cells (Treg) in the tumor

tion of a TLR7 agonist attenuatesand chemotherapy. However, patients

microenvironment. The combinational

regulatory T cells by dendritic cell

who receive such benefits of ICIs aretreatment with PD-L1 blockade further

modification and overcomes resis-

limited and differ by their clinical grade

reduced the tumor’s growth. Resiqui-tance to PD-L1 blockade therapy”

and tumor tissue type.

mod monotherapy and combined treat-

was published in Oncotarget (2018,

To improve the efficacy of ICI treat-ment markedly increased the ratio of9:13301, Nishi N et al. at DOI: org/

ment and to reduce economic toxicity

CD8 T cell/Treg in the tumor. They

10.18632/oncotarget.24327)

by the use of ICIs, the research group

found that systemic low-dose resiqui-

has invented a new way to use the syn-mod administration induced earlier ac-

Summary: TMDU researchers devel-

thetic compound of toll-like receptor 7

tivation of two types of dendritic cells

oped a new use for TLR7 agonists in(TLR7) agonist (resiquimod) as a com-(plasmacytoid and conventional), re-cancer immunotherapy. Systemic ad-

panion drug of ICIs. TLR7 is a member

sulting in the reduced recruitment ofministration of low-dose resiquimod isof the TLR family that recognizes theregulatory T cells and increased recruit-useful as a companion drug with PD-1/

molecular patterns of various microbes.

ment of effector killer T cells in the tu-PD-L1 blockade therapy. This may have

TLR7-mediated signals lead to the acti-mor microenvironment. They further

great potential to eradicate tumors, especially in immunosuppressive tumors

BControlanti-PD-L1 Ab

150

0300

Resiquimod（RQ)

RQ + PD-L1150tion.
Resiquimod
conventionalDCs8bindingto TLR7
plasmacytoidDCs020 01020Days after tumor inoculation

R+P QD-L
1

10Days after tumor inoculation

RQ0draining lymph nodes

Fig.1: The effects of treatments with resiquimod and/or PD-L1 blockade ina SCCVII tumor model
A. Change of tumor volume. Treatments were started on day seven.
B. The ratio of CD8+ T cells/regulatory T cells (Treg) in tumor-infiltrating
lymphocytes (TILs) on day 19.

tumor microenvironment

CD8+ T cells
activation
activation

activation/proliferation ↑regulatory T cells ↓ntPD .
-L10with abundant regulatory T cell infiltra-16CD8+ T/ Treg ratio in TILs

300

CoTumor volume (mm3) Tumor volume (mm3)ACD8+ eﬀector T/ Treg ↑Fig.2: PPossible mechanism of resiquimod action for enhancing anti-tumor
effectSystemic administration of low-dose resiquimod induces a transient andrapid activation of plasmacytoid and conventional dendritic cells,
resulting in enhanced priming of T cells in draining lymph nodes. Tumorrecruiting CD8 + effector T cells increased while regulatory T cells
decreased in the tumor microenvironment.

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