Impact of sex, MHC, and age of recipients on the therapeutic effect of transferred leukocytes from cancer-resistant SR/CR mice

Abstract

BackgroundSpontaneous Regression/Complete Resistant (SR/CR) mice are resistant to cancer through a mechanism that is mediated entirely by leukocytes of innate immunity. Transfer of leukocytes from SR/CR mice can confer cancer resistance in wild-type (WT) recipients in both preventative and therapeutic settings. In the current studies, we investigated factors that may impact the efficacy and functionality of SR/CR donor leukocytes in recipients.ResultsIn sex-mismatched transfers, functionality of female donor leukocytes was not affected in male recipients. In contrast, male donor leukocytes were greatly affected in the female recipients. In MHC-mismatches, recipients of different MHC backgrounds, or mice of different strains, showed a greater negative impact on donor leukocytes than sex-mismatches. The negative effects of sex-mismatch and MHC-mismatch on donor leukocytes were additive. Old donor leukocytes performed worse than young donor leukocytes in all settings including in young recipients. Young recipients were not able to revive the declining function of old donor leukocytes. However, the function of young donor leukocytes declined gradually in old recipients, suggesting that an aged environment may contain factors that are deleterious to cellular functions. The irradiation of donor leukocytes prior to transfers had a profound suppressive effect on donor leukocyte functions, possibly as a result of impaired transcription. The cryopreserving of donor leukocytes in liquid nitrogen had no apparent effect on donor leukocyte functions, except for a small loss of cell number after revival from freezing.ConclusionDespite the functional suppression of donor leukocytes in sex- and MHC-mismatched recipients, as well as old recipients, there was a therapeutic time period during the initial few weeks during which donor leukocytes were functional before their eventual rejection or functional decline. The eventual rejection of donor leukocytes will likely prevent donor leukocyte engraftment which would help minimize the risk of transfusion-associated graft-versus-host disease. Therefore, using leukocytes from healthy donors with high anti-cancer activity may be a feasible therapeutic concept for treating malignant diseases.

Young donor white blood cell immunotherapy induces extensive tumor necrosis in advanced-stage solid tumors

“…Recent studies on the interplay between the immune system and cancer have illustrated that in addition to adaptive immunity, the innate immune system has an inheritable naturally-occurring surveillance and antitumor mechanism capable of recognizing and removing cancerous cells as they are generated over time [ 4 , 5 , 9 , 10 , 11 , 12 , 23 , 24 ]. Prior studies in a colony of cancer-resistant SR/CR mice support the concept that the innate immune system is capable of single handedly protecting a host against cancer in both preventative and therapeutic settings [10] .…”

“…Blanks et al showed that CKA levels in healthy controls was higher than in cancer cases [4] . Stehle Jr et al further demonstrated that young donor leukocytes had greater functionality and performed better [9] . Therefore, the cancer-free history of young and healthy donors and their first-degree relatives was used as a means of donor selection in addition to the other criteria described above.…”

“…Granulocyte transfusions (GT) have been used safely in clinical practice for over 40 years to treat cancer patients with chemotherapy-induced neutropenia and infections [ 6 , 7 , 8 , 9 ]. However, the efficacy of GT as a therapeutic anti-cancer agent was not determined until recent studies in colonies of spontaneous regression/complete resistance (SR/CR) mice and humans suggested that the innate immune system may have a previously unrecognized role in immune surveillance and inheritable cancer resistance [ 4 , 10 ].…”

“…This cancer resistance mechanism is preexisting, independent of T and B lymphocytes, requires no prior cancer exposure, but can be strengthened by repeated tumor cell challenges [11] . Further studies revealed that this CKA is also present in human circulating leukocytes predominantly granulocytes, monocytes, and natural killer (NK) cells with higher antitumor activity in healthy controls versus cancer cases [4] and aging had a profound inhibitory effect on the anticancer activity in SR/CR mice [ 9 , 11 ]. Most importantly, these studies revealed that this innate cancer resistance mechanism was completely transferable to wild type (WT) recipient mice without the SR/CR phenotype either for prevention against subsequent cancer challenges or eradication of established malignancy at distant sites [5] , suggesting that adoptive transfer of human peripheral blood leukocytes to patients with advanced-stage malignancies may potentially represent a new, viable anti-cancer therapy.…”

“…Animal studies have shown that young mice leukocytes resulted in the highest overall cancer survival when challenged with lethal cancerous cells compared to aged donors [9] . These studies also revealed that the loss of CKA with age was primarily due to loss of cancer recognition and migratory function but not necessarily a loss in the number of granulocytes [ 9 , 12 ]. Therefore, it is highly unlikely that an expansion of granulocyte number, i.e.…”