Cancer immunology and radiobiology: Oliver Scott’s struggle for the perfect tumour model in translational research

Abstract

Oliver Scott is best known for his research into the role of tumour hypoxia in radiation oncology. Yet no less important were Oliver’s activities in the development of concepts and methods for performing translational research on the effect of ionising radiation on tumour in experimental animals, stressing the importance of using strictly inbred animals for transplantation of tumours which had arisen in exactly the identical mouse strain. Otherwise residual immunity would lead to uncontrollable bias in the results of cure experiments, invalidating conclusions. These pioneering views are no less valid in today’s cancer research.

Introduction

Oliver Scott is best known for his research into the role of tumour hypoxia in radiation oncology, the underlying physiology, pathology and the development of methods to overcome the radioresistance of hypoxic tumour cells by using hyperbaric oxygen or hypoxic cell radiosensitisers.¹ Yet no less important were Oliver’s activities in the development of concepts and methods for performing translational research on the “effect of ionising radiation on tumour in experimental animals”, to quote the title of one of his longest papers which he wrote only few years after his most famous early study which established hyperbaric oxygen as effective method to overcome the radioresistance of hypoxic tumours.²

In this project in which different members of Hal Gray’s group collaborated it was Oliver’s task to test the hypothesis, that the concept of dissolving oxygen under high pressure in the blood serum would be able to make hypoxic tumour cells radiosensitive. In order to test this hypothesis, Oliver developed a novel method to investigate the therapeutic effect of radiation on mouse tumours in vivo which nowadays is the most frequently employed method in translational radiotherapy research, i.e. the measurement of re-growth delay. The original laboratory protocols and the drawings derived from them have been preserved in his personal archive and they testify the extraordinary care with which the experiments have been designed, performed and documented. It is typical for Oliver’s modesty that he left it to his close friend Hugh Thomlinson who in 1960 made this method popular as it is today.³

Already in his review of the “older literature” Oliver stressed the importance of using strictly inbred animals for transplantation of tumours which had arisen in the particular mouse strain. Otherwise residual immunity would lead to uncontrollable bias in the results of cure experiments. This issue remained one of the most important scientific concerns of Oliver throughout his life. In this review of 1958 he discussed many hypotheses which had been brought forward mostly in the 1930s, e.g. whether spontaneous or transplanted tumours would be preferable as experimental models, and whether the radiation effect on tumours is due to direct radiation-induced tumour cell death or secondary to effects on other components of the tumour tissue. He stated clearly that it is not the early pathological radiation effect that matters but the delayed “loss of reproductive integrity” of what we call today tumour stem cells which determines the therapeutic success.² He extensively discussed also the critical role of residual immunity in inadequate tumour models, concluding that “in many radiation experiments, it would appear likely that the cures obtained were almost entirely due to the immune response of the host, and radiation has only served to tip the balance in the evenly matched struggle between the growth of the tumour and the resistance of the tumour-bearing animal.” And “If, for instance, 99% of the cells of a large inoculum are killed by radiation, small differences in the histocompatibility genes of tumour and host may account for the failure of the remaining 1% to grow.”²

Soon after, these ideas were validated by the work of H.D. Suit in Houston and H. Hewitt in ICRF London. In his private archive, Oliver kept many of Hewitt’s early publications since 1953 most of which carry handwritten dedications in which Hewitt stressed that “one of the more valuable results in this work was to reveal our mutual thoughts and interests.” Yet, while Hewitt was seeking the public arena to fight against speculative promises about the prospects of cancer immunotherapy writing a philippica in 1980 with the title “Immunotherapy of cancer: an underview”—with a note on the reprint: ”To Oliver, another thing we agree about”,⁴ Oliver concentrated on meticulous studies into the details of inbreeding ingeniously using mathematical matrices.⁵ He stressed that 20 generations of inbreeding as has been used before are clearly not sufficient. In a paper “the choice of experimental tumour systems”, he argued that “inbred mice may not be as well-defined genetically as has been supposed”.⁶ Moreover, with the passage of time, both the inbred strain of host animals and the tumour which was isolated from that inbred strain may change. He loved to test his arguments with extensive calculations, in the search for “the impure mouse”.⁷

Few others took these concerns more seriously than H.D. Suit who in his animal house set up the most rigid inbreeding routine, using only tumours for few rounds of transplantation which had arisen spontaneous in aging inbred mice. This way he proved that tumour cure by radiotherapy requires the direct sterilisation of all tumour stem cells and that anti tumour immunity does not contribute to cure.⁸ This is a good example of how Oliver contributed to the progress of translational radiobiology, not by performing massive experiments but by considering the experimental evidence produced by others, drawing his own conclusions, discussing it with friends and writing a plethora of letters to the publishers—and again to friends.

There has been a recent renaissance of interest in tumour immunology, yet claims as to the efficacy of immunotherapy have not been based on convincing evidence of sterilisation of tumour stem cells arising from rigid experiments such as those performed by H.D.Suit and which would have been accepted by Oliver Scott.

He concluded his presidential address as president of the Oncology section of the Royal College of Medicine in 1992 in his typical way asking: “what are the “take-home-messages” of my talk? Let us in future oppose amateurism and striving for short term objectives. Can we accept … that cancer research is a discipline requiring some apprenticeship? Could organisations like ICR, ICRF or NCI lay on a course of at least two years in cancer studies, before workers are allowed to spend a life-time in cancer research? PhD students in a cancer research department are so busy with their specialised project that they simply do not have time to wade through the diffuse literature of the subject, and educate themselves. … Let us hope that the lessons of the past will not be forgotten.”

At a time when translational research in radiation oncology is focussing more and more on xenografted human tumour cell lines, if possible even transplanted orthotopically, but relying on short-term experimental endpoints, a critical mind such as that of Oliver Scott would be urgently needed.