Blocking of cell‐mediated tumor immunity by sera from patients with growing neoplasms

Abstract

Blood lymphocytes from tumor patients can specifically destroy cultivated neoplastic cells of the same histological origin as the tumors of the lymphocyte donors, irrespective of whether or not the donors have symptoms of growing tumor.The purpose of the present study was to investigate whether sera from tumor patients could block the cytotoxic effect of lymphocytes immune to the specific antigens of the respective neoplasms. A wide variety of tumors were included in the tests, namely malignant melanomas, carcinomas of the colon, breast, ovary, endometrium, kidney, cervix uteri, lung, larynx, bladder, Fallopian tube, lip, seminomas Blood lymphocytes from patients with a large variety of tumors can specifically kill the same patients' neoplastic cells in vitro (Hellstrom et al., 1968a(Hellstrom et al., ,b, 1970a(Hellstrom et al., ,b,c, 1971Bubeniketal., 1970a,b). This is often the case also when lymphocytes from patients with one type of neoplasm are tested on morphologically similar tumors from other patients. No such specific cytotoxicity is seen on normal cells or on neoplasms different from those of the lymphocyte donors.A cytotoxic effect can be detected both when the lymphocytes are taken from tumor-bearing patients and when they are derived from patients who have become clinically symptom-free. The former finding may seem paradoxical but is analogous to observations made in animals. There the fact that tumors can grow in vivo although their cells are killed in vitro has been attributed to a specific blocking effect of serum from tumorbearing individuals, which is probably akin to the in viilo phenomenon of immunological enhancement (Hellstrom ef af., 1969;Hellstrom and Hellstrom, 1969, 1970b;Heppner, 1969;Sjogren, 1970). There is recent evidence that a similar serum effect can be demonstrated in certain human tumor cases, such as carcinomas of the colon (Hellstrom et al., , 1970b, neuroblastomas (Hellstrom et al., 1970a), and bladder carcinomas (Bubenik et al., 19706).This study attempts to establish to what extent sera from human patients with a large variety of tumors can block the destruction of Reccived: November 24, 1970. 226 HUMAN TUMOR IMMUNITYneoplastic cells by specifically immune lymphocytes. It also concerns the specificity of the blocking serum activity and whether or not this activity is dependent on the presence of detectable tumors; the latter aspect will be further investigated by more detailed studies on a small group of patients. PatientsTarget tumor cells of a variety of histological types were studied (see the Tables), and normal tissues were obtained from most patients. Lymphocytes were harvested from patients with neoplasms of the same histological type as the target cells used for a given test and from patients with different tumors, from patients with diseases other than cancer, and from healthy subjects.Tumors and normal tissues were explanted following procedures recently described (Hellstrom et al., 1970a). LymphocytesPeripheral blood lymphocytes were used for the...

Suggestive Evidence That the “Blocking Antibodies” of Tumor-Bearing Individuals May Be Antigen-Antibody Complexes

“…Alternatively, one may visualize the blocking factors as antigen-antibody complexes, capable of acting on the target cells, the lymphocytes, or both, any action on the lymphocytes having to be of a temporary nature to account for the finding that lymphocytes from tumor-bearing individuals are specifically reactive in vitro. The second hypothesis is more compatible than the first one with the lack of detectable blocking activity in sera from mice whose (Moloney) virus-induced sarcomas have regressed (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), from rabbits whose (Shope) papillomas have regressed (17), and from mice and rats whose methylcholanthrene-induced and (polyoma) virus-induced sarcomas, respectively, have been removed (18), although such sera do contain antibodies that can bind to the respective type of tumor (16,18) This paper describes experiments with blocking sera from animals bearing progressively growing primary sarcomas induced by Moloney virus or transplanted methyleholanthrene-induced sarcoma (MCA-1050) isografts. The basic plan of the experiments was to try breaking up hypothetical antigen-antibody complexes by subjecting blocking sera to low pH, and subsequently separating their two components by ultrafiltration.…”

“…Progressive tumor growth in vivo, despite a strong cellmediated anti-tumor immunity demonstrable in vitro, has been attributed to a specific ability of the serum of tumorbearing individuals to prevent target cell destruction by immune lymphocytes (2,(6)(7)(8)(9)(10)(11)(12); the mechanisms of the protection may be similar to those of the in vivo phenomenon of immunological enhancement (13). Sera from tumor-bearing animals, but not from tumor-free ones, can also abrogate the migration inhibition seen when peritoneal cell suspensions from specifically immune donors are exposed to tumor-antigen extracts in vitro (14).…”

Detection of Anti-tumour Cell Mediated Immunity and Serum Blocking Factors in Cancer Patients by the Leucocyte Adherence Inhibition Test

“…In recent years, specific cell mediated immunity (CMI) has been demonstrated in human patients towards antigens of their own tumours, by lymphocyte cytotoxicity (Hellstr6m et al, 1968, 197 la), lymphocyte transformation (Vanky et al, 1971) and macrophage migration inhibition (Andersen, Bendixen and Schi0dt, 1969). Circulating anti-tumour antibodies have been detected by several methods, notably immunofluorescence (Lewis et al, 1969) and complement-dependent cytotoxicity (Hellstrom et al, 1968); antibody-like blocking factors (BF), which interfere with CMI, are now well known in association with tumour growth (Hellstrom et al, 1971b(Hellstrom et al, , 1973Halliday, 1972;Hellstrom and Hellstrom, 1973a, b).…”

Clinical Relevance of Circulating Immune Complexes in Human Leukemia

“…It is obvious that they are most often insufficient to adequately control the malignant cell proliferation. Interference of humoral factors with the cell-mediated response of the patient to his neoplasm has been proposed as an explanation ofthe failure ofthe immume system to control tumor growth, and this is supported by the demonstration in vitro of a specific blocking of lymphocyte-mediated cytotoxicity by the serum of individuals with growing tumors (10,14,15). There is evidence that serum blocking factors may consist of immune complexes (16)(17)(18)(19).…”