SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling

Abstract

DC-based tumor vaccine research has largely focused on enhancing DC maturation/costimulation and antigen presentation in order to break tolerance against self tumor-associated antigens. DC immunization can activate autoreactive T cells but rarely causes autoimmune pathologies, indicating that self tolerance at the host level is still maintained in the vaccinated hosts. This study in mice reveals a novel regulatory mechanism for the control of self tolerance at the host level by DCs through the restriction of positive cytokine feedback loops by cytokine signaling inhibitor SOCS1. The study further finds the requirement of persistent antigen presentation by DCs for inducing pathological autoimmune responses against normal tissues and tumor, which can be achieved by silencing SOCS1 to unleash the unbridled signaling of IL-12 and the downstream cytokine cascade. However, the use of higher-affinity self peptides, enhancement of DC maturation, and persistent stimulation with cytokines or TLR agonists fail to break tolerance and induce pathological antitumor immunity. Thus, this study indicates the necessity of inhibiting SOCS1, an antigen presentation attenuator, to break self tolerance and induce effective antitumor responses.

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

“…In a study of an animal model of melanoma, continuous TLR2, 3, 4, or 7 stimulation elicits cytotoxic T-cell generation, but no in vivo effect on anti-tumor responses reflected by uninterrupted tumor growth and no signs of autoimmunity (vitiligo) in treated animals can be observed. Additional modification of the TLR signaling pathway including SOCS1 inhibition in DCs induces effective anti-melanoma immunity with marked IL-12 secretion and visible tumor growth suppression [104]. Moreover, genetic immunization along with TLR ligation is not efficient enough in the treatment of melanoma in mice, suggesting the existence of active tumor immunotolerance.…”

Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity

“…Some of the well-recognized tumor immune evasion mechanisms include failure of tumor antigen recognition (4-6), modulation of MHC molecule expression (7,8), improper activation of antigen-presenting cells (APC; refs. 1, 9), failure of lymphocyte homing (1,10), and production of immunosuppressive cytokines (11,12). These immunologic abnormalities associated with the tumor microenvironment either inhibit the priming of antitumor adaptive immunity (1) or tolerize tumor-specific CD4 (13,14) and CD8 (15,16) T cells.…”

SOCS1 downregulation in dendritic cells promotes memory T-cell responses

“…Previous work has shown that IL-12 signaling is enhanced when SOCS1 is downregulated in T cells and DCs [17,35]. IL-12 is required for induction but not maintenance of memory T1 (type 1 T cell) responses [24].…”

“…The suppressor of cytokine signaling 1 molecule (SOCS1) controls signaling of many cytokines, including IFN-γ, IFN-α, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-15, and IL-21 utilizing a feedback loop mechanism [10][11][12][13][14][15][16][17][18][19]. First, binding of a cytokine to its receptor upregulates expression of SOCS1.…”