Imbalances in cellular immunological parameters in blood predetermine tumor onset in a natural mouse model of breast cancer

Abstract

The development of new approaches to breast cancer (BC) early diagnosis is an important objective of modern oncology. Although the role of the immune system in cancer initiation process was experimentally well established, the prognostic value of cellular blood immunological parameters (CBIPs) for BC onset prediction was not demonstrated either in clinics or in mouse models. In this study, we focused on revealing informative CBIPs for mammary cancer (MC) onset prediction in the BLRB/BYRB mouse model with a high incidence of natural MC development. Blood samples were collected from 80 aging females of these original mouse strains, 12 basic CBIPs were estimated by flow cytometry. Then mice were followed up for 28 weeks, and the outcome of females (MC diagnosis, death without MC or MC-free survival) was registered. We estimated the patterns of changes in CBIPs with age and in accordance with the outcome. An increasing imbalance in 11 CBIPs during natural aging of females clearly resembled human immunosenescence phenomenon and several patterns corresponded to the results obtained on cancer-free members of BC-affected families. We stratified heterogeneous female population into middle-aged and old subgroups. Low NK-cell levels in middle-aged mice and low B-cell along with high T-helper levels in old mice distinguished females with developed MC from the other groups. We found a reliable correlation of several CBIPs with age at MC diagnosis and survival of cancer-bearing females. Thus, we demonstrated the predictive potential of CBIPs as a basis for the development of prognostic models for BC onset in clinics.

Keywords: Breast cancer; Cellular blood immunological parameters; Immune system; Mouse model.

Fig. 1

The lowest initial level of NK cells was observed in a subgroup of middle-aged females with diagnosed MC (MC⁺, triangles) relative to those dying without MC (died MC⁻, squares), and females alive after 28 weeks of observation without MC symptoms (alive MC⁻, circles). Mean values are shown as columns, SEM—as whiskers

Fig. 2

Initial levels of B cells (open columns) and T-helpers (striped columns) in a subgroup of old mice. Mice with diagnosed MC (MC⁺, triangles) were characterized by a combination of reduced B cells relative to the group of surviving MC⁻ females (circles) and increased T-helpers relative to deceased MC⁻ females (squares). Mean values are shown as columns, SEM—as whiskers

Fig. 3

Initial levels of B cells (a) and NK cells (b) in females diagnosed with MC at different ages. MC-bearing females with earlier onset were characterized by a lower initial level of B cells and a higher initial level of NK cells relative to MC-bearing mice with later onset. Mean values are shown as columns, SEM—as whiskers

Fig. 4

Survival of MC-bearing mice (a) and scatter plot of age at MC diagnosis against survival time (b). Both short survivors (open triangles) and long survivors (closed triangles) could be found among females with earlier and later tumor manifestation

Fig. 5

The level of several initial blood immunological parameters of MC-bearing mice with short and long survival. Short survivors were characterized by higher levels of T cells (a), T-helpers (b), activated T-helpers (c), and by diminished levels of B cells (d) relative to long survivors. Mean values are shown as columns, SEM—as whiskers