"The best way of exterminating the wicked cells that we may have in our bodies is to encourage the good ones. They will kill the others better than we can."

Investigators in determining the function of an organ or a type of cell have as a rule resorted to indirect methods. Much information has been gained from the study of pathological conditions, where function has been interfered with, or by study of deficiencies after the removal of an organ. Rarely has it been possible to vary experimentally the size or activity of an organ or tissue, conditions which would yield more or less direct evidence of function.

The lymphoid tissue considered as an organ has been particularly difficult to investigate. It not only composes largely the spleen and numerous lymph nodes but small deposits are scattered through most of the organs and tissues of the body and in addition large numbers of the cells are to be found in the circulation. If all this tissue could be brought together in a single mass it would represent an organ of considerable size. It is not surprising that removal of the spleen, the largest single deposit, representing however only a fraction of the total, is so quickly compensated for that no definite deficiencies are detectable.

Heteroplastic Tissue Grafting. - The association of the lymphoid type of cell with the mechanism by which an animal prevents the growth of an implanted tissue from another species and which eventually brings about the death of foreign cells is a subject which has long attracted the attention of pathologists. The possibility of utilizing the tissues of related species in human repair surgery and in organ deficiencies has been attempted even on a large scale. In spite of certain reported successful clinical results, the consensus of opinion is that it is impossible to graft tissues from one species to another in the higher animals and that rarely does such grafting succeed from one individual to another even of the same species. The very sensitive mechanism through which an organism rejects the cells of another species even though those cells be capable of supplying a real deficiency in some vital function is as yet little understood.

In Section I we have reviewed several theories which have been brought forward to explain tissue specificity but none of these have stood the test of adequate investigation. While the new evidence presented here is not intended to furnish a basis for a new theory, it does suffice to indicate that the round cell infiltration so characteristic of the reaction to foreign tissue grafts is a purposeful reaction and that these cells are the agent through which the mechanism exerts its force. The evidence on which this conclusion is based is as follows: 

    It is probable that the majority of intact normal animals possess sufficient lymphoid tissue to combat a cancer graft, but in the susceptible animal the mechanism by which these cells are attracted to the locality of the graft is for some reason imperfect. Some of the experiments quoted in Section V show that even in susceptible animals where a sufficient local lymphoid reaction is induced, by processes unrelated to general resistance, a high degree of local resistance results. Precisely what the mechanism is which determines whether or not a local reaction is to take place about a cancer graft and how the lymphocyte exerts its influence on the cancer cell are points on which we have been able to gain no light.

Resistance to Neoplasms in Other Species. - Although the main facts of our investigation have been arrived at through the study of mice, selected because of their great susceptibility, there is considerable evidence from other sources that the relationship between lymphoid reaction and cancer resistance is not confined to this species. Ribbert (1) called attention to the association between the round cell reaction and retrogressing areas in human cancer, and more recently MacCarty (2) has demonstrated the prognostic importance of the amount of lymphoid infiltration, particularly in breast cancer.

The histological study of the fate of grafts of transplantable tumors of rats (3), chickens (4), and rabbits has shown that the local lymphoid reaction is just as constant an accompaniment of resistance as it is in mice. Varying the lymphoid content by means of x-ray has been shown to exert the same influence on the fate of rat tumors as it does with mouse cancer. The recent studies of Ewing (6) and of Alter (7) indicate that the cell reaction induced by x-ray and radium is probably the intermediate agent in bringing about the favorable therapeutic result in human cancer, a conclusion analogous to the one we arrived at from the study of mouse cancer. In view of all these observations it would seem that the association of the cellular reaction with resistance to neoplastic growths is not a peculiarity of the mouse and also that the results could be duplicated in other species than those studied.

    The question as to why cancer metastases grow so regularly in the lymph nodes, particularly in man, is a point which has not yet been adequately investigated. The dissemination to the lymph node is probably a mechanical affair. One possible explanation of the growth of the cancer in the presence of antagonistic cells, is that the lymphocyte as it exists in the node is inactive and is capable of functioning only when it migrates into the tissues. There is a somewhat analogous phenomenon in the polymorphonuclear leucocyte, which is unable to perform one of its important functions, i.e. phagocyting, inside the vessels. 

    Another explanation, more plausible and with some supporting evidence, is that the lymph node only becomes the seat of an active metastasis when it has become exhausted. In addition to this consideration there seems little doubt that the lymphogenic function of an involved node is largely obliterated and the number of lymphoid cells is markedly decreased as the growth progresses. There is at present not sufficient evidence at hand to answer the question inasmuch as it has not been studied from this point of view.

    The mechanism by which the various agents bring about stimulation of the lymphoid system and induce resistance to cancer is a point on which we have no direct knowledge. One suggestive fact only is available to indicate a possible explanation, namely that the serum collected from an animal after an exposure to x-ray or dry heat has a definite stimulating action on lymphoid cells in vitro. From this fact it may be assumed that some chemical change has been produced in the body fluids which in turn is capable of acting on the lymphoid cell. The presence of a stimulative substance in the blood of oil-injected animals or those treated with homologous tissue has not been tested, so that there is wanting evidence for a more general conclusion on this point.

    In this connection it is of interest to note, a propos of the recent discussion of whether or not x-ray exerts stimulative properties, that our studies have demonstrated beyond doubt that this physical agent under proper conditions may induce a real stimulation of an animal tissue.

    Other questions similar to the above which have not been subjected to experimental verification because of their comparative unimportance may be mentioned. One finds occasionally among the mice with spontaneous tumors a disease similar to lymphatic leucemia and a like condition has been described in man. Under these circumstances there seems no more reason to expect the abnormal lymphocyte to perform its normal function than for a cancer cell to produce a normal secretion. 

    We have also noticed that an animal with an initial high lymphocyte count is no more apt to be resistant than one with a low count. Presumably the normal number of these cells in the circulation is maintained to meet the requirements of the animal. When called on to meet an additional burden, such as an inoculation with cancer, the degree of success seems to depend on the ability of the animal to produce more cells and the animal with a low initial count is just as apt to react as one with a high count. The production of a blood lymphocytosis without stimulation of the lymphogenic tissue, particularly the transitory lymphocytosis following the administration of certain drugs, is without effect on the resistance to cancer. This is not surprising when it is considered that the increase in numbers of the cells is caused by contraction of the spleen with a forcing out of the lymphocytes m the pulp spaces and that these quickly disappear from the circulation.

Bearing of These Studies on the X-Ray Therapy of Cancer.- In the course of our study of the function of the lymphoid tissue, certain points have been developed, incidentally, which seem to have a bearing on x-ray therapy of cancer and may at least offer an explanation of some of the clinical results from this form of treatment.

    An occasional observation has been noted of instances where malignant tumors have apparently grown more rapidly and disseminated more freely after x-ray treatment. This fact has led to a controversy as to whether under certain conditions x-ray may not actually stimulate tumor cells rather than destroy them. So far there has been no experimental evidence to support this idea, but in Section III we have shown that doses of x-ray sufficient to deplete the lymphoid system, definitely lower an animal's resistance to implanted tumor. This is true more or less regardless of the type of resistance, whether it be natural, induced, or acquired. 

    May not some such interference with the defensive mechanism result from the intense x-ray dosage used in man? There is no doubt that the amount of irradiation used in some cases is sufficient to reduce the circulating lymphocytes to a point indicating a very widespread destruction of this tissue and at least comparable to the condition in mice representing a state of reduced resistance to cancer.

    If it be true that the human cancer cell is no more susceptible to an x-ray than the mouse cancer cell (8), and there is very good reason to believe that this is true, how is one to account for the high percentage of cures in certain types of skin cancer? If this result depended on an unusual degree of sensitiveness of this group of cancer to the direct action of x-ray, it would be expected that the metastatic cells in a superficial lymph node would be almost as easily influenced by the ray as the cells in their original location, but this is not true. The dose of x-ray utilized in the treatment of skin cancer is given over too small an area to induce any general effect on resistance of the type described in mice.

    The experiments described in Sections V and VI offer an explanation which at least has some experimental basis. The x-ray treatment, as shown by these tests, confers a local immunity on the exposed skin and renders it an unsuitable soil for the support of tumor growth. This resultant refractory state was found to be confined to the skin layers and did not extend even to the underlying connective tissue (see Text-fig. 23). The cellular reaction resulting from the treatment was also confined to the skin layers. This result led us to suggest that the therapeutic action of x-ray in cancer depended on the cellular reaction induced in the normal tissues surrounding the growth.

    This idea was more exhaustively tested with spontaneous cancers of mice. Cancers growing in the skin disappeared promptly after a mild erythema dose of x-ray, but if after exposure in situ the tumor was removed and replanted in an unexposed area of skin in the same animal, growth progressed as uninterruptedly as if no x-ray had been given. A histological study of the fate of a cancer graft inoculated into an area previously exposed to x-ray, shows a series of degenerative changes identical with those which have been repeatedly described as the result of the direct action of x-ray on the cancer cells. Yet these particular cells had received no x-ray.

    While there is not conclusive evidence that the above observations would hold true for man, practically the only study on human material carried out from this point of view supports the idea of the importance of the induced cellular reaction. Ewing based his investigation on a large number of cases treated with both x-ray and radium and concludes that there is little or no evidence of direct destruction of cancer cells, but that the subsequent cellular exudate appears to exert a damaging effect on the neoplasm. He considers the latter as an essential factor in the curative process.

To summarize: there is no evidence that cancer cells are more easily destroyed by x-ray than normal cells; x-ray in a mild erythema dose renders the exposed area highly resistant to a subsequent cancer implant; this resistance seems to depend on the amount of cellular reaction induced; x-ray in large generalized doses definitely lowers an animal's resistance to implanted cancer.

GENERAL CONCLUSION

BIBLIOGRAPHY

1. Ribbert, H., Das Karzinom des Menschen, Bonn, 1911, 195.

2: MacCarty, W. C., Surg., Gynec. and Obst., 1914, xviii, 284.

4. Rous, P., and Murphy, Jas. B., J. Exp. Med., 1912, xv, 270.

5. Mottram, J. C., and Russ, S., Proc. Roy. Soc. London, Series B, 1917-19, xe,

1; Russ, S., Chambers, H., Scott, G. M., and Mottram, J. C., Lancet, 1919, cxcvi, 692.

7. Alter, N. M., J. Med. Research, 1919, xl, 241.

8. Hill, B., Morton, J. J., and Witherbee, W. D., J. Exp. Med., 1919, xxix, 89.