Centrosome dysfunction: a link between senescence and tumor immunity

Abstract

Centrosome aberrations are hallmarks of human cancers and contribute to the senescence process. Structural and numerical centrosome abnormalities trigger mitotic errors, cellular senescence, cell death, genomic instability and/or aneuploidy, resulting in human disorders such as aging and cancer and affecting immunity. Interestingly, centrosome dysfunction promotes the secretion of multiple inflammatory factors that act as pivotal drivers of senescence and tumor immune escape. In this review, we summarize the forms of centrosome dysfunction and further discuss recent advances indicating that centrosome defects contribute to acceleration of senescence progression and promotion of tumor cell immune evasion in different ways.

Fig. 1

Mechanisms of centrosome aberrations in cancer. The mechanisms of centrosome number abnormalities include duplication cycle dysfunction, centrosome overduplication, mitotic disorder and entosis. These processes result in the formation of invadopodia and establishment of an extra centrosome-associated secretory phenotype (left). The mechanisms of structural centrosome abnormalities include changes in the amounts of centrosome components, abnormal localization of core proteins, and aberrant binding among core proteins; these changes lead to cell extrusion and dissemination of mitotic cells (right)

Fig. 2

Centrosome aberration-associated molecular pathways in cellular senescence. Oxidative stress and several stress-associated regulators activate p53 via phosphorylation (forming phosphorylated p53, P-p53) to stimulate the translocation of p53 to centrosomes or promote its degradation. Phosphorylation of centrosomal p53 subsequently triggers the activation of proteins that modulate the onset of senescence. In addition, dissociation of pericentrin or PCM-1 induces permanent exit from the cell cycle that is accompanied by an increase in the expression of cellular β-galactosidase, a hallmark of cellular senescence. Similarly, disruption of other PCM components, such as Cep192 (which recruits NEDD1 to the PCM) and NEDD1 (which recruits γ-tubulin to the PCM), leads to centrosome fragmentation and premature entry into the senescence pathway. The scissors indicate that p53 cannot translocate into centrosomes

Fig. 3

Centrosome aberrations trigger an immunosuppressive microenvironment. Centrosome aberrations can result in the accumulation of double-stranded DNA (dsDNA) in the cytosol. The presence of cytosolic dsDNA activates the cGAS–STING pathway. In cancer cells with centrosome dysfunction, however, alternative inflammatory STING-dependent signaling, such as NF-κB signaling, is activated. Chronic NF-κB activation has been shown to mediate the extra centrosome-associated secretory phenotype (ECASP) by affecting proteins including IL-8, GDF-15 and ANGPTL4. IL-8 is also one of the components of the senescence-associated secretory phenotype (SASP); it recruits Th2 cells and M2 macrophages to shape the immunosuppressive microenvironment. Additionally, centrosome aberrations contribute to decreased tumor neoantigen expression and mutagenesis, thereby suppressing MHC class I antigen presentation and decreasing CD8+ T cell infiltration to enable evasion of antitumor immune responses. Ultimately, centrosome abnormalities can lead to immune escape, distant metastasis and therapeutic resistance