Excess of the NF-ĸB p50 subunit generated by the ubiquitin ligase KPC1 suppresses tumors via PD-L1– and chemokines-mediated mechanisms

Yelena Kravtsova-Ivantsiv; Gilad Goldhirsh; Alexandra Ivantsiv; Ofer Ben Itzhak; Yong Tae Kwon; Eli Pikarsky; Aaron Ciechanover

doi:10.1073/pnas.2019604117

New Research In

Contributed by Aaron Ciechanover, October 4, 2020 (sent for review September 18, 2020; reviewed by Ivan Dikic and Yosef Shiloh)

Significance

Recruitment of the immune system to suppress malignant tumors can involve different mechanisms, including inhibition of suppressive immune checkpoints (the enemy of my enemy is my friend), generation of specific CAR-T cells that recognize tumor cells, and immunization against the patient’s tumor antigens. Here we describe a mechanism, where excess of the p50 subunit of the NF-ĸB transcription factor that when pairs with another subunit—p65—is oncogenic, but when generated in excess over p65 and as a result homodimerizes, it suppresses tumors. It appears to act via several mechanisms: it stimulates expression of other cancer suppressors, it inhibits generation of the immune inhibitor PD-L1 (thus unleashes the immune system), and it initiates secretion of chemokines, which are chemical attractants of immune cells.

Abstract

Nuclear factor–ĸB (NF-ĸB) transcription factor is a family of essential regulators of the immune response and cell proliferation and transformation. A typical factor is a heterodimer made of either p50 or p52, which are limited processing products of either p105 or p100, respectively, and a member of the Rel family of proteins, typically p65. The transcriptional program of NF-ĸB is tightly regulated by the composition of the dimers. In our previous work, we demonstrated that the ubiquitin ligase KPC1 is involved in ubiquitination and proteasomal processing of p105 to generate p50. Its overexpression and the resulting high level of p50 stimulates transcription of a broad array of tumor suppressors. Here we demonstrate that additional mechanisms are involved in the p50-mediated tumor-suppressive effect. p50 down-regulates expression of a major immune checkpoint inhibitor, the programmed cell death-ligand 1 (PD-L1), both in cells and in tumors. Importantly, the suppression is abrogated by overexpression of p65. This highlights the importance of the cellular quantities of the two different subunits of NF-ĸB which determine the composition of the dimer. While the putative p50 homodimer is tumor-suppressive, the “canonical” p50p65 heterodimer is oncogenic. We found that an additional mechanism is involved in the tumor-suppressive phenomenon: p50 up-regulates expression of the proinflammatory chemokines CCL3, CCL4, and CCL5, which in turn recruit into the tumors active natural killer (NK) cells and macrophages. Overall, p50 acts as a strong tumor suppressor via multiple mechanisms, including overexpression of tumor suppressors and modulation of the tumor microenvironment by recruiting active immune cells.

Footnotes

↵¹Y.K.-I. and G.G. contributed equally to this work.
↵²To whom correspondence may be addressed. Email: aaroncie{at}technion.ac.il.

Author contributions: Y.K.-I., G.G., A.I., and A.C. designed research; Y.K.-I., G.G., and A.I. performed research; Y.K.-I., G.G., A.I., O.B.I., and E.P. contributed new reagents/analytic tools; Y.K.-I., G.G., O.B.I., Y.T.K., E.P., and A.C. analyzed data; and Y.K.-I., G.G., Y.T.K., E.P., and A.C. wrote the paper.
Reviewers: I.D., Goethe University Medical School; and Y.S., Tel Aviv University.
The authors declare no competing interest.