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

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.

Keywords: PD-1; T cell; cancer; immunotherapy; self-nonself discrimination; subtractive hybridization.

Figure 1

A hypothesis about the physiological function of programmed death-1 (PD-1): Demarcation of the border between ‘slightly altered self’ and ‘nonself’. (A) Originally, when we are young, the border between ‘self’ and ‘nonself’ is obvious. (B) However, subtle changes gradually accumulate as cells age, and the self-nonself border becomes ambiguous. In order to avoid the attacking against ‘slightly altered’ aged somatic cells by the exquisitely evolved immune system of higher vertebrates, we obtained PD-1. Here, PD-1 functions to widen and re-define the border between ‘slightly altered self’ in aged individuals and ‘nonself’. Cancer cells are clever enough to sneak into this chink between the original self and the slightly altered self, so that they can be protected by PD-1 and avoid the immune-cell attack. (C) When we block the activity of PD-1, the self-nonself border moves back (closer) to the original one, and a fraction of cancer cells (and also aged somatic cells) get re-defined as nonself, allowing the highly evolved immune system to attack them.