PD-1: Its Discovery, Involvement in Cancer Immunotherapy, and Beyond.

Yasumasa Ishida

doi:10.3390/cells9061376

Abstract

On December 10, 2018, I was sitting among the big crowd of audience, as one of the invited guests to the ceremony, in the Stockholm Concert Hall. When King of Sweden Carl XVI Gustaf bestowed the diploma and medal of Nobel Prize of Physiology or Medicine 2018 on Dr. Tasuku Honjo and shook his hand for a while, surrounded by the thunderous applause and energetically blessing orchestral music, I thought that it had been a long journey for the molecule that we had first isolated in the early 1990s. Although it was truly a commemorable moment in the history of the programmed death-1 (PD-1) research, I believe we still have a long way to go. In this review article, I will explain why I think so, particularly by focusing on the potential role(s) that PD-1 appears to play in self-nonself discrimination by the immune system.

Highlights

In the early 1990s, a novel gene was discovered in Kyoto University, Japan, in search for the molecular mechanisms involved in self-nonself discrimination by the immune system [1]
In 1989, a UK team showed that self-reactive immature T lymphocytes (T cells) in the thymus undergo programmed cell death [2]. This observation led the Kyoto University researches to assume that, if they are able to discover the genes strongly associated with the deaths of immature T cells, some of them would become good candidates for the key molecules playing pivotal roles in self-nonself discrimination
One gene was discovered at that time in a challenging screening experiment in molecular biology, and the gene was named programmed death-1 (PD-1), with a hope that it would be somehow involved in the apoptosis-inducing processes of self-reactive immature T cells [1]

Summary

Introduction

In the early 1990s, a novel gene was discovered in Kyoto University, Japan, in search for the molecular mechanisms involved in self-nonself discrimination by the immune system [1]. In 1989, a UK team showed that self-reactive (potentially harmful) immature T lymphocytes (T cells) in the thymus undergo programmed cell death (apoptosis) [2] This observation led the Kyoto University researches to assume that, if they are able to discover the genes strongly associated with the deaths of immature T cells, some of them would become good candidates for the key molecules playing pivotal roles in self-nonself discrimination. One gene was discovered at that time in a challenging screening experiment in molecular biology, and the gene (or its product) was named programmed death-1 (PD-1), with a hope that it would be somehow involved in the apoptosis-inducing processes of self-reactive immature T cells [1] It turned out, several years later, that the novel molecule had nothing to do with the induction of programmed cell death/apoptosis [3,4,5,6]. PD-1 was not directly involved in the cell death-inducing processes (despite its ominous name), it could still be playing crucial roles in self-nonself discrimination, as initially expected in the early 1990s

Historical Background

Self-Nonself Discrimination and T-Cell Deaths

Cell-Death Research in the Early 1990s

Discovery of PD-1

The PD-1 Research in the Honjo Laboratory in the Late 1990s

Recent Developments in Cancer Immunotherapy