研究所

トップページ研究所研究分野紹介腫瘍免疫応答研究分野Division of Immune Response

Division of Immune Response

Introduction


Our primary research interest is to develop effective, safe and off-the-shelf adoptive cancer immunotherapy to cure patients with advanced cancer. In this therapy, T cells that specifically recognize tumor antigens are prepared in vitro and infused back into the patient. Peripheral blood T cells are genetically engineered with tumor antigen-specific T cell receptor (TCR) or chimeric antigen receptor (CAR) to specifically attack tumor cells. Recent clinical trials have demonstrated great efficacy of adoptively transferred CAR-T cells targeting the B-cell antigen CD19.

However, the CAR-T cell therapy against solid tumors has not been successful at similar levels. In addition, even anti-CD19 CAR-T cells are not curative for some types of B cell malignancies. Moreover, we need to address serious side effects associated with the immune response and the huge costs required for individual preparation of antitumor T cell grafts. We aim to improve adoptive cancer immunotherapy by solving these problems. Our overarching goal is to cure cancer by using the immune system.

Research topics

Adoptive immunotherapy is a promising therapeutic option for patients with advanced cancer. Tumor antigen-specific T cells are generated and expanded in vitro, and the antitumor T cells are adoptively transferred into the patient. Patients’ derived peripheral blood mononuclear cells (PBMC) are most often used as a T-cell source. Although T cells in the peripheral blood are polyclonal, they are easily transduced with tumor antigen-specific T cell receptor (TCR) or chimeric antigen receptor (CAR) and efficiently expanded by anti-CD3 monoclonal antibody and cytokines (Fig. 1). Antitumor T cells can also be obtained by tumor-infiltrating lymphocytes (TIL) in certain types of cancer. Recent studies have already shown that CAR-T cell therapy targeting CD19 is highly effective for B cell malignancies such as acute lymphoblastic leukemia and diffuse large cell B-cell lymphoma (Maude et al. N Engl J Med 2018;, Locke et al. Lancet Oncol 2019; Schuster et al. N Engl J Med 2019), which is now approved in the United States, Europe, Canada, Australia, and Japan. However, the CAR-T cell therapy against solid tumors has not provided satisfactory treatment efficacy (Li et al. J Hematol Oncol 2018). It has also been noted that a substantial number of patients treated with the anti-CD19 CAR-T cells suffer from relapse (Fraietta et al. Nat Med 2018). In addition to its limitation in the efficacy, we frequently experience serious side effects due to systemic immune response and huge costs required for individual preparation of antitumor T cell grafts. We are currently performing multiple projects to solve these problems.

Figure 1. Overview of adoptive immunotherapy. Antitumor T cells that specifically recognize tumor are prepared in vitro and infused into the patient.

T cell modification to enhance its longevity as well as effector functions

To improve treatment effects of adoptive immunotherapy, we aim to understand and regulate two features acquired by antitumor T cells: differentiation and exhaustion (Fig. 2). Dr. Restifo and colleagues at NCI demonstrated that memory T cell differentiation is closely related to persistence of the infused T cells, which is more important than transient effector functions in terms of durable therapeutic efficacy (Gattinoni et al. J Clin Invest 2005; Gattinoni et al. Nat Med 2011). Although the differentiation of memory T cells inevitably progresses accompanied by T cell proliferation, it can be regulated by modifying specific molecular or signaling pathways. We reported that epigenetic manipulation or curtailed anti-CD3 activation of T cells contributes to maintaining an immature memory T cell phenotype: stem cell-like memory T cells (TSCM) and central memory T cells (TCM) during in vitro expansion (Kagoya et al. J Clin Invest 2016; Kagoya et al. JCI Insight 2017).
Another important concept associated with antitumor immunity is T cell exhaustion, which is defined as attenuation of effector functions such as cytokine secretion and proliferative capacity in T cells chronically exposed to the antigenic stimulation. It is now established that blockade of PD-1 successfully reactivates endogenous antitumor T cells in various types of cancer. However, you can also think about why the exhaustion system is equipped in our T cells. It may be required for survival of T cells when they are continuously exposed to the target antigen. In fact, knockout of PD-1 or its regulator TOX does not necessarily result in better control of chronic viral infections or tumor progression in mouse models (Odorizzi et al. J Exp Med 2015; Scott et al. Nature 2019). In addition, fully exhausted T cells acquire unique epigenetic profiles that cannot be reverted by PD-1 blockade (Pauken et al. Science 2016).
These previous studies indicate that both T cell differentiation and exhaustion result from genome-wide alteration of epigenetic and/or gene expression profiles in T cells. We aim to elucidate these fundamental molecular mechanisms and apply the findings to the development of T cells with durable antitumor effects in any type of cancer.

Figure 2. Both memory T cell differentiation and exhaustion need to be addressed to induce durable clinical response by antitumor T cells. TSCM: stem cell-like memory T cell; TCM: central memory T cell; TEM: effector memory T cell.

Regulation of side effects such as cytokine release syndrome

Adoptive immunotherapy is accompanied by various side effects, in which cytokine release syndrome (CRS) and neurological toxicities are ones of the most frequent and serious complications (Fig. 3). These events are induced by cytokines such as IL-6 and IL-1b, which are produced by macrophages activated by T cells (Norelli et al. Nat Med 2018; Giavridis et al. Nat Med 2018). Since the risk for CRS development increases as antitumor response improves, we need to address these adverse events in parallel with therapeutic efficacy. We aim to incorporate a mechanism that attenuates the severity of CRS in antitumor T cells themselves.

Figure 3. Endogenous macrophages activated by antitumor T cells secrete IL-6 and IL-1b, which are considered to be associated with the development of cytokine release syndrome and neurological toxicities, respectively.

Development of the system to make adoptive immunotherapy more universal and versatile

Recent studies have shown that the efficacy of CAR-T cell therapy is highly dependent on the quality of the infused T cells. For example, CAR-T cells derived from healthy donors controlled progression of the leukemia cell line engrafted in immunodeficient mice much better than the CAR-T cells generated from the patients with chronic lymphocytic leukemia (Fraietta et al. Nat Med 2018). Since antitumor T cell grafts are individually generated by using the patients-derived T cells in most of the cases, heterogeneity of the quality of T cells may result in unstable treatment effects.
Huge costs required for individual preparation of the T cell grafts are another problem that hampers widespread use of this therapy. Although the Bispecific T-cell Engager (BiTE) Blinatumomab, which connects the anti-CD3 mAb with the anti-CD19 mAb to confer antileukemic activity to endogenous T cells, has been used in the clinic, its effect seems to be weaker than that induced by the CAR-T cells. We aim to develop “artificial system” that mimics T cell-mediated cytotoxicity applicable to any patient. Successful completion of this project will enable T cell therapy to be a more universal and off-the-self approach.

Members

Tsukasa Nabekura
Post
Chief
Tsukasa Nabekura
Post
Chief
Tajima
Post
Research Assistant
Mizuho Enomoto
Post
Research Assistant
Mizuno
Post
Administrative Assistant

Publications

  1. Yoshikawa T, Wu Z, Inoue S, Kasuya H, Matsushita H, Takahashi Y, Kuroda H, Hosoda W, Suzuki S, Kagoya Y. Genetic ablation of PRDM1 in antitumor T cells enhances therapeutic efficacy of adoptive immunotherapy. Blood in press. DOI: 10.1182/blood.2021012714
  2. Kagoya Y, Guo T, Yeung B, Saso K, Anczurowski M, Wang CH, Murata K, Sugata K, Saijo H, Matsunaga Y, Ohashi Y, Butler MO, Hirano N. Genetic ablation of HLA class l, class ll, and the T cell receptor enables allogeneic T cells to be used for adoptive T cell therapy. Cancer Immunol Res. 2020;8(7):926-936.

Selected Peer-Reviewed Papers

  1. Kagoya Y, Saijo H, Matsunaga Y, Guo T, Saso K, Anczurowski M, Wang CH, Sugata K, Murata K, Butler MO, Arrowsmith CH, Hirano N. Arginine methylation of FOXP3 is crucial for the suppressive function of regulatory T cells. J Autoimmun. 2019;97:10-21.
  2. Kagoya Y, Nakatsugawa M, Saso K, Guo T, Anczurowski M, Wang CH, Butler MO, Arrowsmith CH, Hirano N. DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models. Nat Commun. 2018;9:1915.
  3. Anczurowski M, Yamashita Y, Nakatsugawa M, Ochi T, Kagoya Y, Guo T, Wang CH, Rahman MA, Saso K, Butler MO, Hirano N. Mechanisms underlying the lack of endogenous processing and CLIP-mediated binding of the invariant chain by HLA-DP84Gly. Sci Rep. 2018;8:4804.
  4. Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, Saso K, Butler MO, Minden MD, Hirano N. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med. 2018;24:352-359.
  5. Guo T, Koo MY, Kagoya Y, Anczurowski M, Wang CH, Saso K, Butler MO, Hirano N. A Subset of Human Autoreactive CD1c-Restricted T Cells Preferentially Expresses TRBV4-1+ TCRs. J Immunol. 2018;200:500-511.
  6. Yamashita Y, Anczurowski M, Nakatsugawa M, Tanaka M, Kagoya Y, Sinha A, Chamoto K, Ochi T, Guo T, Saso K, Butler MO, Minden MD, Kislinger T, Hirano N. HLA-DP(84Gly) constitutively presents endogenous peptides generated by the class I antigen processing pathway. Nat Commun. 2017;8:15244.
  7. Kagoya Y, Nakatsugawa M, Ochi T, Cen Y, Guo T, Anczurowski M, Saso K, Butler MO, Hirano N. Transient stimulation expands superior antitumor T cells for adoptive therapy. JCI Insight. 2017;2:e89580.
  8. Chamoto K, Guo T, Scally SW, Kagoya Y, Anczurowski M, Wang CH, Rahman MA, Saso K, Butler MO, Chiu PP, Julien JP, Hirano N. Key Residues at Third CDR3β Position Impact Structure and Antigen Recognition of Human Invariant NK TCRs. J Immunol. 2017;198:1056-1065.
  9. Kagoya Y, Nakatsugawa M, Yamashita Y, Ochi T, Guo T, Anczurowski M, Saso K, Butler MO, Arrowsmith CH, Hirano N. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J Clin Invest. 2016;126:3479-3494.
  10. Nakatsugawa M, Rahman MA, Yamashita Y, Ochi T, Wnuk P, Tanaka S, Chamoto K, Kagoya Y, Saso K, Guo T, Anczurowski M, Butler MO, Hirano N. CD4(+) and CD8(+) TCRβ repertoires possess different potentials to generate extraordinarily high-avidity T cells. Sci Rep. 2016;6:23821.
  11. Morita K, Masamoto Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, Kurokawa M. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia. 2015;29:2248-2256.
  12. Iizuka H, Kagoya Y, Kataoka K, Yoshimi A, Miyauchi M, Taoka K, Kumano K, Yamamoto T, Hotta A, Arai S, Kurokawa M. Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis. Exp Hematol. 2015;43:849-857.
  13. Nishikawa S, Arai S, Masamoto Y, Kagoya Y, Toya T, Watanabe-Okochi N, Kurokawa M. Thrombopoietin/MPL signaling confers growth and survival capacity to CD41-positive cells in a mouse model of Evi1 leukemia. Blood. 2014;124:3587-3596.
  14. Kagoya Y, Yoshimi A, Tsuruta-Kishino T, Arai S, Satoh T, Akira S, Kurokawa M. JAK2V617F+ myeloproliferative neoplasm clones evoke paracrine DNA damage to adjacent normal cells through secretion of lipocalin-2. Blood. 2014;124:2996-3006.
  15. Kagoya Y, Nannya Y, Nakamura F, Kurokawa M. Gene expression profiles of central nervous system lymphoma predict poor survival in patients with diffuse large B-cell lymphoma. Br J Haematol. 2014;166:794-797.
  16. Sato T, Goyama S, Kataoka K, Nasu R, Tsuruta-Kishino T, Kagoya Y, Nukina A, Kumagai K, Kubota N, Nakagawa M, Arai S, Yoshimi A, Honda H, Kadowaki T, Kurokawa M. Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Oncogene. 2014;33:5028-5038.
  17. Ueda K, Yoshimi A, Kagoya Y, Nishikawa S, Marquez VE, Nakagawa M, Kurokawa M. Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16. Cancer Sci. 2014;105:512-519.
  18. Nukina A, Kagoya Y, Watanabe-Okochi N, Arai S, Ueda K, Yoshimi A, Nannya Y, Kurokawa M. Single-cell gene expression analysis reveals clonal architecture of blast-phase chronic myeloid leukaemia. Br J Haematol. 2014;165:414-416.
  19. Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, Kobayashi H, Saito T, Iwakura Y, Kurokawa M. Positive feedback between NF-kappaB and TNF-alpha promotes leukemia-initiating cell capacity. J Clin Invest. 2014;124:528-542.
  20. Kagoya Y, Kataoka K, Nannya Y, Kurokawa M. Pretransplant predictors and posttransplant sequels of acute kidney injury after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:394-400.

Education & Training

We are seeking highly motivated researchers in PhD or postdoctoral training. Candidates are expected to be engaged in studying basic T cell biology as well as developing a novel therapeutic in the field of adoptive cancer immunotherapy. For postdoctoral fellows, previous experience in molecular biology, biochemistry or immunology will be considered as an advantage.

Recruitment Announcement