Peripheral blood lymphocytes from a total of 373 tumor patients were tested by either a colony inhibition or a cytotoxicity test for cell-mediated immunity against human neoplasms of various histological types. Lymphocytes from 51 of 59 patients studied (88%) either reduced colony numbers formed by plated autochthonous tumor cells or were cytotoxic to them, and lymphocytes from 78 of 87 patients tested (89%) had a similar effect on allogeneic tumor cells of the same histological type as those of the lymphocyte donors. Evidence indicating antigenic cross-reactivity between tumors of the same histological type was obtained for the following seven groups of neoplasms: malignant melanomas, carcinomas of the colon, breast, testis, endometrium and ovary, and various sarcomas. Lymphocytes affecting tumor cells had no effect on normal cells from the same patient, or on cells from other types of neoplasms than the target cells under study.



The degree of cell-mediated immunity, as detectable with the techniques employed, was approximately the same in patients having active neoplastic disease as in patients who were clinically symptom-free. Eleven of 12 patients who were tested after having been symptom-free for more than 2 years had a lymphocyte-mediated anti-tumor immunity.



Mise en Evidence D'une Immunite A Mediation Cellulaire Envers les Neoplasmes Humains de Divers Types Histologiques



Nous avons etudie des lymphocytes du sang peripherique de 373 cancereux au moyen de tests d'inhibition des colonies et de cytotoxicite en vue de mettre en evidence une immunite a mediation cellulaire envers les neoplasmes humains de divers types histologiques. Les lymphocytes de 51 des 59 sujets etudies (88%) ont fait diminuer le nombre de colonies formees par les cellules tumorales autochtones ou se sont montres cytotoxiques a l'egard de ces cellules; les lymphocytes de 78 des 87 sujets testes (89%) ont eu un effet analogue sur les cellules tumorales allogeneiques du měme type histologique que celles des donneurs de lymphocytes. Nous avons obtenu la preuve de l'existence d'une reactivite antigenique croisee entre les tumeurs du měme type histologique pour les 7 groupes de neoplasmes suivants: melanomes malins, epitheliomas du colon, du sein, des testicules, de l'endometre et des ovaires, et divers sarcomes. Les lymphocytes agissant sur les cellules tumorales n'ont pas eu d'effet sur les cellules normales du měme malade, ni sur les cellules de neoplasmes de types histologiques differents.



Le degre d'immunite a mediation cellulaire decele au moyen des techniques utilisees etait a peu pres le meme chez les malades atteints d'une neoplasie active que chez les sujets ne presentant aucun symptǒme clinique. Nous avons observe une immunite antitumorale a mediation lymphocytaire chez 11 des 12 malades qui ont ete testes apres ětre restes asymptomatiques pendant plus de deux ans.

Demonstration of cell-mediated immunity to human neoplasms of various histological types.

Sera from mice carrying progressively growing sarcomas induced by Moloney virus or methylcholanthrene can block the cytotoxic effect of lymphocytes immune to the tumor-specific antigens of the respective neoplasms. The blocking effect can be specifically removed by absorbing sera with the respective types of tumor cells, and it can be recovered from these cells by elution at low pH. If the low pH is maintained, it is possible to separate out a low and a high molecular weight fraction from the eluates. If the fractions are added to the target cells for 45 minutes and then removed, neither of these fractions can block lymphocyte-mediated cytotoxicity, while a 1:1 mixture of them has a specific blocking effect. If they are admixed with the lymphocytes, incubated for 1 hr, and then allowed to incubate with the target cells and lymphocytes during the entire 2 days of the test, the low molecular weight fraction, as well as the mixture, but not the high molecular weight fraction, has a blocking activity. It is suggested that the blocking factor in sera from tumor-bearing animals, as regularly tested, is an antigen-antibody complex, capable of binding to the target cells and/or reacting with lymphocytes immune to their antigens, thus blocking the lymphocytes' reactivity; the latter reaction is postulated to be of a temporary nature.

Suggestive evidence that the "blocking antibodies" of tumor-bearing individuals may be antigen--antibody complexes

Publisher Summary This chapter reviews the evidence for cell-mediated immune reactions against tumors in animals and man, particularly, the reactions that can lead to destruction of neoplastic cells cultivated in vitro. Various mechanisms by which tumor cells can escape from immunological destruction have been discussed, most notably one involving blocking factors, present in the serum. Findings analogous to those obtained when studying tumor immunity (coexistence of cell-mediated reactivity and blocking serum activity) have been summarized from three other areas (pregnancy, allografting, and chimeras). The studies reviewed in the chapter have given a relatively large amount of evidence for various cell-mediated and humoral immunological reactions against growing tumors, and at least some of the reactions observed in vitro appear to be able to influence tumor growth in vivo .

Lymphocyte-Mediated Cytotoxicity And Blocking Serum Activity To Tumor Antigens

Publisher Summary This chapter discusses the cytotoxic effects of lymphoid cells in vitro. The chapter discusses the complex problem of different types of cytotoxic effects of lymphoid cells. These outstanding workers in the field have managed to present a cohesive picture of the various effects on the target cells. The role of “nonspecific” factors is particularly well clarified. The interrelationships among contact lysis, release of pharmacologically active substances, and the terminal components of the complement system are given in the chapter for special consideration. In an in vitro model, it is shown that lymphoid cells from sensitized donors destroy tissue culture cells carrying the antigen to which the cell donor is sensitized. This type of cytolytic reactions is encountered in a great variety of immune situations, comprising all those mentioned in the chapter. The cell that initiates in vitro cytotoxic reaction is assumed to be the sensitized lymphocyte, equipped with its own recognition sites for antigen on the cells that are destroyed. Although this may be true in many situations, it now seems clear that “normal” lymphoid cells can become cytotoxic to other cells by a variety of pathways. The study of the various pathways by which lymphoid cells can become cytotoxic has been helpful for the understanding of effector role of these cells in cell-destructive reactions in general.

Cytotoxic effects of lymphoid cells in vitro.

Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Neuroblastoma

The combined effect of immune lymphocytes (lymphnode cells or blood lymphocytes) and serum from tumor-bearing donors was assessed in four tumor systems with the use of the colony inhibition assay: (a) Moloney virus-induced sarcomas in mice, (b) Shope papillomas in rabbits, (c) spontaneous mammary carcinomas in mice, and (d) two adenocarcinomas of the colon and two adenocarcinomas of the lung in humans. The neoplasms studied had previously been shown to possess tumor-specific antigens, against which cellular immunity could be detected in vitro. In all four systems, it was found that sera from hosts with progressively growing neoplasms could abrogate the inhibitory effect of lymphocytes which were immune to the specific antigens of the corresponding tumor type. Studies with Moloney sarcomas, in particular, showed that the serum effect had at least some degree of specificity.

Gloria H. Heppner

Papers

Serum-mediated protection of neoplastic cells from inhibition by lymphocytes immune to their tumor-specific antigens