The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 255

including free radicals, cytokines, and growth factors that negatively affect
cancer immuno-editing by impeding the proliferation and/or function of
CD4 þ and CD8 þ T cells. The immunosuppressive microenvironment in
tumors also stimulates the generation and/or promotion of immunosuppres-
sive cells such as type 2 macrophages, myeloid-derived suppressor cells,
immature dendritic cells, and regulatory T lymphocytes. 402,403,409,410
Both primary and secondary lymphoid organs including thymus, spleen,
and lymph nodes are intensively innervated by ANS and NES. 411-416 Under
normal physiological conditions, the production of cytokines and cytolytic
factors, proliferation of leukocytes, activities of NK cells, and redistribution
of T and B lymphocytes, dendritic cells, leukocytes, and macrophages to
lymphoid organs, all follow a robust circadian rhythm in vivo . 195,417-424 Dis-
ruption of circadian homeostasis is closely related to immune suppression. 425
Ablation or deregulation of the core circadian genes Per1 , Per2 , Bmal1 , Rev-
erba

,or Clock in mice induces an array of abnormalities in the immune sys-
tem, including the deregulation of proinflammatory cytokines, cytotoxic
receptors, immunoregulatory genes, and NK and mast cell activities, and
inhibition of B lymphocyte differentiation. 164,180,183,184,192,193,196,418,426
Mice lacking both Cry1 and Cry2 display constitutive elevation of
proinflammatory cytokines and are prone to chronic inflammation, a com-
mon underlying mechanism for cancer. 106 Importantly, the immune func-
tion is not controlled at the cell autonomous level in vivo . Consecutive
phase-advance shifts of environmental light cues disrupt the molecular clock
and circadian homeostasis of NK cell function in rats. 427 Ablation of sym-
pathetic innervation abolishes the circadian oscillation of cytokines and
cytolytic factors in splenocytes and NK cells, 374 hematopoietic stem cell traf-
ficking, and the expression of chemokine CXCL12. 375 Adoptive transfer of
Bmal1 / bone marrow deficient in B lymphocyte differentiation to lethally
irradiated BALB/c Rag2 / recipients that are unable to generate mature
B lymphocytes due to lack of V(D)J recombination activating gene 2
( Rag2 ) resulted in normal T and B lymphocyte differentiation from
Bmal1 / bone marrow. However, reciprocal transfer of BALB/c
Rag2 / bone marrow to lethally irradiated Bmal1 / mice did not lead
to normal B lymphocyte development, suggesting that the SCN control
of tissue microenvironment in bone marrow plays a dominant role in lym-
phocyte precursor proliferation and differentiation in vivo . 180
The central pacemaker controls the function of the immune system, but
it can also be modulated by immune products such as proinflammatory cyto-
kines interleukin 1 and 6 (IL-1 and IL-6), tumor necrosis factor- a (TNF- a )