Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

Abstract

The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.

Human Tregs at the materno-fetal interface show site-specific adaptation reminiscent of tumor Tregs

“…Also, others have reported that nonlymphoid tissue Tregs display an activated phenotype compared with lymphoid organ and circulating Tregs ( 12 , 20 , 73 ). Both BATF and the TNFRSF/NF-κB signaling axis are crucial in the survival of Tregs and maintenance of a stable effector Treg phenotype, especially in tissues ( 15 , 28 , 32 , 33 , 78 , 79 , 101 ). It is now recognized that Tregs adapt to their tissue environments, with, on the one hand, common adaptations across many tissues — such as increased expression of IL10, IL1RL1 (encoding ST2, an IL-33 receptor subunit), AREG (encoding amphiregulin), CTLA4, TIGIT, BATF, and IRF4 and decreased expression of LEF1, TCF7 — but, on the other hand, importantly, tissue-specific signatures ( 12 , 13 , 15 , 16 , 18 ).…”

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…Both hyperactive Notch1 and Notch3 enhances CXCR4 expression in thymus-derived and in BM-derived T-cells in T-ALL [106,107], and CXCR4 silencing inhibited the expansion of leukemic cells [106] through disruption of the Notch/CXCR4 partnership [102]. Of note, NFκB enhanced generation of Treg, suppressing the antitumor immune response in a Notch3-dependent T-ALL mouse model [108]. In AML, the activation of CXCR4 is critical for the migration and retention of leukemia cells within the BM, for extramedullary metastasis, chemotherapy resistance [109], and for the maintenance of minimal residual disease (MRD) [110].…”

Human regulatory T cells at the maternal-fetal interface show functional site-specific adaptation with tumor-infiltrating-like features

“…Also others have found that non-lymphoid-tissue Tregs display an activated phenotype compared to lymphoid-organ and circulating Tregs, 13,18,80 and both BATF and the TNFRSF-NF-κB signaling axis have been described as crucial in the survival of Tregs and maintenance of a stable effector Treg phenotype, especially in tissues. 16,28,32,33,85,86,108 It is now recognized that Tregs adapt to their tissue environments, with common adaptations across many tissues, such as increased expression of IL10, IL1RL1 (encoding ST2, an IL-33 receptor subunit), AREG (encoding amphiregulin), CTLA4, TIGIT, BATF and IRF4, and a low expression of LEF1 and TCF7 compared to lymphoid tissue Tregs, but, importantly, also tissue-specific signatures. 12,13,16,17,21 These tissue-specific transcriptomic profiles counter the notion that tissue Tregs merely have a more activated, effector or memory state than lymphoid-organ Tregs.…”