Life science
Medical & healthcare, Drug development

Development of a novel cancer immunotherapy
by targeting regulatory T cells
Department of Frontier Research in Tumor Immunology, Graduate School of Medicine
Specially Appointed Professor Naganari Ohkura
https://researchmap.jp/read0007148?lang=en!!"#$%&$&'()%*%)+,,-$(.'/(&&(0$12$3451/6%2*%,3/+3%27$8/(7&Regulatory T cells (Tregs) are essential for immune homeostasis and maintain homeostasis by negatively regulating excessive
immune responses. Because of this property, removal of Tregs isthought to be effective in strengthening cancer immunity, yet at thesame time, there is concern that it may also increase the risk of autoimmune diseases. Therefore, in order to induce strong anti-tumor
immunity while avoiding autoimmune diseases, we attempted to
selectively remove tumor-infiltrating Tregs. First, we identified thechemokine receptor CCR8 as a molecular target specific to tumor-infiltrating Tregs. In tumor-bearing mouse models, CCR8-targeted Treg
removal demonstrated strong anti-tumor immunity while avoiding
autoimmune diseases. Furthermore, in these individuals, long-term
anti-tumor immune memory was also established. Based on theseresults, we have developed a human anti-CCR8 antibody, and are
now conducting a clinical trial of the antibody against solid tumors.

Lymph nodes
OrgansTumorsBlood!!"#$%&'(%))*+,!"#$▍ Background & Results
Regulatory T cells (Treg) are essential for immune homeostasis
and maintain homeostasis by negatively regulating abnormal orexcessive immune responses. This characteristic of Tregs makes
their control effective in suppressing autoimmune diseases, and inenhancing cancer immunity. Therefore, we attempted to develop a
new therapy for cancers by focusing the diversity of Tregs.
Previous studies have shown that Treg removal can enhanceanti-tumor immune activity. However, since systemic Treg removal
can cause severe autoimmune diseases, its application to cancer
therapy requires a trick to enhance only anti-tumor immune activity
while avoiding the onset of autoimmune diseases. One possible
solution to the problem is cell removal targeting only tumor-infiltrating Tregs. Therefore, we searched for cell surface molecules thatare specific to tumor-infiltrating Treg cells. Single-cell analysis oftumor-infiltrating T cell fractions isolated from human clinical specimens revealed the chemokine receptor CCR8 as a membranesurface molecule with high specificity for tumor-infiltrating Tregcells. In tumor-bearing mouse models, administration of anti-CCR8
antibody demonstrated potent anti-tumor immune activity whileevading autoimmune disease. Furthermore, in about half of theseindividuals, complete elimination of cancer was achieved, andlong-term anti-tumor immune memory was also established. Theseresults indicate that selective elimination of Tregs may become anew cancer immunotherapy. We are now conducting a clinical trialof a human anti-CCR8 antibody against several solid tumors.

▍ Significance of the research and Future perspective
Cancer immunotherapy has been established as the fourth therapeutic modality, but its response rate is still low and its application
is limited depending on the cancer types. On the other hand, anti-CCR8 antibody has shown broad efficacy against various solid
tumors in tumor-bearing mouse models, and the synergistic effects
with immune checkpoint inhibitors have also been observed. These
characteristics suggest that this therapy may be effective for awider range of cancer types. We hope that selective Treg removal
will become a new therapeutic approach that enables complete
cancer remission.

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Abstract

1500

Lung

Isotype control

1000Control

500!CCR80051015ColonPancreas**!CCR820100 µm

Fig 2

By selective removal of tumor antigen-specific Tregs
long-term anti-tumor immune memory is established
Normal Treg removal

CCR8-targetedTreg removal

Tumor antigenspecific Treg

Tumor
microenvironment
Normal Treg

Treg reduction

Recovery by
immune homeostasis
Go back to theinitial state

Recovery with a lack oftumor antigen-specific Tregs

Establishment of long-term immune memory

Supplementary Figure

P a t e n t JP6501171, US10550191, CN110573180, AU2018243020, KR10-2144658, RU2730984, JP6894086, RU2782462.
Kidani, Yujiro et al. CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting
Tr e a t i s ememory. Proc Natl Acad Sci U S A. 2022, 119(7), e2114282119. doi: 10.1073/pnas.2114282119
URL
K e y w o r d regulatory T cells, CCR8, cancer immunotherapy, autoimmune disease