How to target cancer mitotic regulators in to enhance immune recognition

The past decade has been notable for the advancement of immunotherapy in treating many advanced cancers, particularly immune checkpoint blockade. However, a clinical response to immune checkpoint blockade across solid tumours is observed in only 20–40 % of patients. Recently, it has been demonstrated that activation of the nucleic acid sensor cyclic GMP-AMP synthase (cGAS) plays a major role in tumour immunosurveillance . Activation of the cGAS-STimulator of INterferon Genes (STING) innate immune pathway in the tumour microenvironment has been reported to regulate numerous tumour-immune interactions such as acquisition of an ‘immunologically hot’ phenotype which stimulates immune-mediated elimination of transformed cells. Therefore, an attractive therapeutic strategy has been the concept of exogenously inducing cGAS-STING in cancer using DNA damaging therapies. However, manipulation of the spindle assembly checkpoint (SAC) may be a complementary approach that could exhibit beneficial synergy with immune checkpoint therapy or other immunotherapies.

On average, approximately 330 billion new cells are generated every day in the human body. Therefore, it is crucial that the replicated genetic material is evaluated for its quality at every stage of the cell cycle. The majority of DNA damage is repaired rapidly with few consequences to undergoing DNA transactions by lesion-specific factors. However, damage which is more complex in nature requires activation of cell cycle checkpoints which typically facilitate a temporary halt in cell cycle progress permitting an organised DNA damage response (DDR) to occur. The SAC is a signalling pathway which functions in M phase of the cell cycle to prevent unequal distribution of the replicated genetic material between two daughter cells.

Fig. 1



Spindle assembly checkpoint (SAC) signalling. In prometaphase, recruitment of SAC proteins to unattached chromosome centromeres result in sequestration of cytoplasmic CDC20 and formation of mitotic checkpoint complex (MCC); this hinders activation of APC/C and triggers a temporary hiatus in mitotic progression. In metaphase, establishment of kinetochore-microtubule attachment and adequate inter-kinetochore tension facilitates SAC disassembly and release of CDC20 from MCC inhibition. In anaphase, APC/CCDC20 activity enables liberation of separase from a complex with securin; this leads to cohesin ring cleavage and sister chromatin separation. APC/CCDC20-mediated proteasomal degradation of cyclin B inactivates CDK1 and promotes mitotic exit.


Effective anti-mitotics in standard clinical use include the chemotherapeutic family of taxanes, such as paclitaxel. Traditionally, paclitaxel’s mechanism of action has been defined by its anti-proliferative activity, nonetheless, a significant amount of data suggest that paclitaxel can also work as an immunomodulator of TME. For example, paclitaxel has been shown to revert the immunologically cold tumour status by stimulating polarisation of macrophages towards the pro-inflammatory M1 phenotype and inducing apoptosis of T regulatory cells (Tregs). Moreover, paclitaxel has been confirmed to provoke tumour immunogenic cell death (ICD) by promoting antigen presentation and enhancing recruitment of CD8?+?T cells and NK cells.

Some data suggest that clinically relevant doses of paclitaxel kill tumour cells by inducing multipolar spindle-mediated chromosome missegregation rather than a prolonged mitotic arrest. As cytoplasmic DNA is a recurrent consequence of defects in mitotic division, a question arises: is immunomodulatory effect of paclitaxel attributed to activation of cGAS-STING? Indeed, it has been shown that expression of functional cGAS and IRF3 is crucial for response to paclitaxel in xenograft cancer models. Subsequent studies have determined that paclitaxel directly induces formation of micronuclei which leads to activation of cGAS-STING and recruitment of tumour-infiltrating lymphocytes (TILs). These data were later corroborated in cells treated with eribulin – an anti-mitotic drug belonging to the microtubule destabilisers class.

Despite excellent initial response to paclitaxel, drug resistance and drug-related toxicity, such as myelosuppression and peripheral neuropathy, inevitably limit the effectiveness of subsequent treatments. Therefore, combination of ICIs with an anti-mitotic agent could expose camouflaged, immunologically cold cancer cells and mitigate the limitations of current immunotherapy regimens. Combined treatment might also help overcome resistance to paclitaxel as STING-driven IFN expression is associated with a corresponding upregulation of PD-L1 in the tumour microenvironment.


Cancer immunotherapy has dramatically transformed the field of oncology by improving survival and quality of life for patients. As immune checkpoint blockade moves towards first line treatment for some cancers, there remains a significant proportion of patients who do not benefit from immune-based therapeutics. To address this problem, ICIs are now being trialled in combination with standard chemotherapeutic regimens including anti-mitotics such as paclitaxel. The synergy of paclitaxel and anti-PD-1/PD-L1 combination has been demonstrated in phase III clinical trials and has been attributed to induction of cGAS-STING signalling which sensitises tumour cells to immune-mediated elimination. Importantly, recent data suggest that a method of paclitaxel formulation in the drug cocktail might be of the essence. Data collected from IMpassion130 and IMpassion131 clinical trials have showed that atezolimumab (anti-PD-L1 agent) in combination with nab-paclitaxel but no paclitaxel prolongs survival of triple-negative breast cancer patients. This result might be attributed to the fact that nab-paclitaxel contains nanoparticles of albumin-bound paclitaxel and its administration does not require concomitant steroid treatment due to significantly lower toxicity when compared to unconjugated paclitaxel.

It should be considered that established cancers, particularly in the metastatic setting, typically present a hostile immune microenvironment that may require additional pre-clinical research in optimisation therapeutic approaches. Therefore, pre-clinical assessment of new anti-mitotics should be associated with identification of relevant biomarkers which could predict treatment outcomes as well as consideration of window-of-opportunity studies which may enable study of these therapies in an early cancer setting.