Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Abstract

29Mutations in the p53 tumor suppressor occur very frequently in human cancer. 30Often, such mutations lead to the constitutive overproduction of mutant p53 31 (mtp53) proteins, which can exert a cancer-promoting gain-of-function (GOF). We 32 have identified a novel mechanism by which mtp53 controls both cell-autonomous 33 and non-cell autonomous signaling to promote cancer cell survival and suppress 34 tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic 35 DNA sensing machinery, cGAS-STING-TBK1-IRF3, that controls the activation of 36 the innate immune response. We find that mtp53, but not wildtype p53, binds to 37 TANK binding protein kinase (TBK1) and inhibits both its basal and agonist-38 induced activity. The association of mtp53 with TBK1 prevents the formation of a 39 trimeric complex between TBK1-STING-IRF3, which is required for activation, 40 nuclear translocation and transcriptional activity of IRF3. Mtp53 knockdown 41 restores TBK1 activity, resulting in the transcriptional induction of IRF3 target 42 genes and IRF3-dependent apoptosis. Furthermore, inactivation of innate immune 43 signaling by mtp53 alters cytokine production resulting in immune evasion. 44 Restored TBK1 signaling was sufficient to bypass mtp53 and reactivate cell-45 autonomous and non-cell autonomous tumor control. Thus, overriding mtp53's 46 inhibition of this cytosolic DNA sensing pathway may ultimately lead to restored 47 an oncogenic mtp53 protein that exhibits gain-of function activities.(5) Recently, it has been 62 reported that 91% of cancers that have a mtp53 allele have lost their second allele through 63 mutation or chromosomal loss.(6) Furthermore, the presence of mtp53 correlates with increased 64 chromosomal instability leading to loss of tumor suppressor genes and amplification of 65 oncogenes.(6, 7) 66 Aneuploidy is considered one of the hallmarks of cancer and is thought to play an 67 important role in driving tumor cell evolution.(8) Aneuploidy has been shown to provoke cell 68 cycle arrest, senescence, increased pro-inflammatory cytokine production and upregulation of 69 Natural Killer (NK) cell ligands in tumor cells, resulting in their subsequent killing by NK 70 cells.(9) In an in vivo setting, the increased production of pro-inflammatory cytokines coupled 71 with increased NK cell ligand expression permits the recruitment of immune cells and clearance 72 of abnormal cells.(10) Thus, in addition to the cell-autonomous mechanisms that suppress 73 genetic instability, cells also utilize non-cell autonomous mechanisms to signal their own 74 destruction.(9) However, chromosomal instability can give rise to micronuclei, which are prone 75 to rupturing and releasing the DNA into the cytoplasm.(11) DNA leaked into the cytoplasm is 76 recognized by the DNA binding protein, cyclic GMP-AMP synthase (cGAS), which in turn triggers 77 innate immune signaling that results in the production of type I interferons.(12) Mechanistically, 78 DNA promotes cGAS homodimerization and production of the secon...

Immune pathways and TP53 missense mutations are associated with longer survival in canine osteosarcoma

“…Higher pre-treatment monocyte counts were previously reported to be associated with a shorter DFI in OSA patients 66 . Ghosh et al 67 reported that mutant p53 reduces the activity of the cytoplasmic DNA sensing cascade which upregulates IFNB1 to stimulate CD8 + , CD4 + , and NK cells, while suppressing M2-tumor associated macrophages 67 . However, we found no difference in IFNB1 expression between tumors bearing mutant, wildtype, or truncated TP53 (ANOVA pvalue: 0.435).…”

TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment

“…Augmented ECM deposition is not the only means whereby mutp53 keeps cytotoxic immune cells away from the cancer cells. In particular, while this paper was under revision, mutp53 was reported to inhibit immune cell infiltration by interacting with TANK binding protein kinase 1 (TBK1) and blunting the cGAS/ STING pathway (56). Hence, mutp53 enlists multiple mechanisms…”

Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma

“…[23][24][25][26] Importantly, recent studies have highlighted the impact of TP53 mutations on immune escape and promotion of an immunosuppressive microenvironment that might be the primary driver of the poor prognosis in this molecularly defined subset. 22,[38][39][40] Taken together, these tumor cell intrinsic factors may also be associated with disease progression, but may also be interlinked with a diminished effector T-cell profile and thus represent a poor prognostic factor per se.…”