Immune-checkpoint inhibitors and CAR-T cell therapy opened the era of immuno-regulatory therapy. We are trying to develop innovative immuno-regulatory therapies against various diseases such as cancer and autoimmune diseases based on the understanding of the regulatory mechanisms of immune system.
Elucidate the regulatory mechanisms of immune system
The 2018 Nobel Prize in Physiology or Medicine was awarded to Drs. Tasuku Honjo and James P. Allison for their discovery of cancer therapy by inhibition of negative immune regulation. They demonstrated that the targeted blockade of inhibitory co-receptors, PD-1 and CTLA-4 can destroy tumors by activating tumor-specific T cells. I have engaged in researches such as the identification of PD-1 ligands, elucidation of the inhibitory mechanism of PD-1, dissection of the pathomechanisms of autoimmune diseases that PD-1KO mice develop, and treatments of cancer by PD-1 blockade in Dr. Honjo’s laboratory. Through these researches, PD-1 has been established as an inhibitory co-receptor of lymphocytes and proposed to be a promising target of cancer immunotherapy.
Stimulatory and inhibitory co-receptors tightly control the activation of lymphocytes by regulating the quality and the quantity of the antigen receptor signaling to optimize beneficial immune responses while avoiding autoimmunity and excess immune responses. In addition to PD-1 and CTLA-4, many other co-receptors have been identified and regarded as potential drug targets. Although these co-receptors are supposed to have unique function and cooperate each other, their functional differences and coordination remain to be clarified. The primary aim of our laboratory is to elucidate the molecular and cellular mechanisms of PD-1 as well as other co-receptors in the regulation of immune responses. By fully understanding the regulatory mechanisms of immune system, we believe we can manipulate immune responses precisely to control various diseases such as cancer and autoimmune diseases.
- Shimizu K, Sugiura D, Okazaki IM, Maruhashi T, Takegami Y, Cheng C, Ozaki S, and Okazaki T. PD-1 imposes qualitative control of cellular transcriptomes in response to T cell activation. Mol Cell, in press.
- Okamura H, Okazaki IM, Shimizu K, Maruhashi T, Sugiura D, Mizuno R, Okazaki T. PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions. J Autoimmun, 105:102296, 2019.
- Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, and Okazaki T. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science, 364:558-566, 2019.
- Mizuno R, Sugiura D, Shimizu K, Maruhashi T, Watada M, Okazaki IM, and Okazaki T. PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Front Immunol, 10:630, 2019.
- Maruhashi T, Okazaki IM, Sugiura D, Takahashi S, Maeda TK, Shimizu K, and Okazaki T. LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol, 19:1415-1426, 2018.
- Okazaki T, Chikuma S, Iwai Y, Fagarasan S, and Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol, 14:1212-1218, 2013.
- Okazaki T, Okazaki IM, Wang J, Sugiura D, Nakaki F, Yoshida T, Kato Y, Fagarasan S, Muramatsu M, Eto T, Hioki K, and Honjo T. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J Exp Med, 208:395-407, 2011.
- Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, and Honjo T. Autoantibodies against cardiac troponin I are responsible for the dilated cardiomyopathy in PD-1 deficient mice. Nat Med, 9:1477-1483, 2003.
- Okazaki IM, Kinoshita K, Muramatsu M, Yoshikawa K, and Honjo T. The AID enzyme induces class switch recombination in fibroblasts. Nature, 416:340-345, 2002.
- Okazaki T, Maeda A, Nishimura H, Kurosaki T, and Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA, 98:13866-133871, 2001.
Graduate School of Medicine