Therapy-induced senescence: friend and foe? - PDF Version
Senescence occurs when cells stop dividing and enter a state of permanent growth arrest and resistance to apoptosis. It is a part of natural ageing. Senescent cells secrete factors known as senescence-associated secreted phenotypes (SASPs), which strongly influence the tissue microenvironment, particularly the immune system. New research shows that senescence also occurs during chemotherapy, radiotherapy, and cancer treatment that targets small molecules. SASPs are released in the tumour microenvironment and affect the outcome of cancer treatment.
A study by Chaib et al. (2002) shows how chemotherapy (in this case, through the use of doxorubicin) and targeted therapies (through the use of palbociclib, cyclin-dependent kinase (CDK)4/6 inhibitor) induce therapy-induced senescence (TIS) with induction of the immune checkpoint protein PD-L2 but not of PDL-L1, which is a close homologue. Tumours deficient forPD-L2 in mice grow slower, develop fewer senescent cells and respond better to chemotherapy than do wild-type tumours. In the Chaib et al. (2002) study, further chemotherapy did not induce the usual senescent markers (the CDK inhibitor CDKN1A, P21, and senescence-associated SAßGAL) in PD-L2-knockout tumours. These data indicate that PD-L2 in tumour cells is required to induce the SASPs and that impaired SASP expression reduces tumour growth. Finally, the elimination of PD-L2+ senescent cells from doxorubicin-treated human melanoma xenografts through the use of a monoclonal anti-PD-L2 antibody led to a substantial delay in tumour growth. Depletion of CD8+ T cells (but not CD4+ T cells) led to suppression of the anti-PD-L2 effect. CD8 suppression was caused by PD-L2-dependent recruitment of immunosuppressive CD11b/Gr1+ myeloid cells.
While these studies support the role of anti-PD-L2 as a senolytic, a recent study from the same research group shows that TIS may also promote an anti-tumour immune response. Using RNA sequencing, Marin et al. (2022) identified cell-surface molecules that were associated with antigen presentation through major histocompatibility complex class I molecules (adaptive immune response) and an interferon transcriptional response signature that was strongly enriched upon TIS (doxorubicin) in the same tumour model with normal fibroblasts. Treatment with doxorubicin-induced senescence in normal fibroblasts and cancer cells with upregulated adenosine triphosphate and calreticulin and, upon injection in vivo, enhanced the recruitment of CD8 T immune cells, both ex- and in vivo. A comparison of doxorubicin-induced immunogenic cell death and doxorubicin-induced senescence demonstrated that senescence was much more potent in terms of antigen presentation by dendritic cells and resulted in prolonged CD8 activation. Indeed, vaccination of tumour-bearing mice with senescent tumour cells, but not with an immunogenic cell death tumour cell vaccine, strongly inhibited primary tumour growth and induced systemic anti-tumour response that protected against rechallenge with different cancer cells. Moreover, senescent cancer cells in human patients were found to hyper-stimulate autologous tumours that had infiltrated reactive T-cells.
Thus, contrary to previous studies from the same group, this finding supports the idea that senescent cells can trigger an efficient anti-tumour immune response. These contrasting results may be due to the different experimental setups that were used. Chaib et al. looked within the immunosuppressive tumour microenvironment at the role of emergent senescent PD-L2+ cells, while Marin et al. studied the capability of senescent cells in a non-tumour immune permissive environment to become highly immunogenic in order to induce a systemic immune response to block tumour growth at another site. Indeed, when cancer cells and senescent cells are co-injected, tumours can form more rapidly than when one is injected by itself (Krtolica et al., 2015).
Beyond cancer, TIS also plays a crucial role in normal tissue. Simona Parrinello showed that senescent fibroblasts disrupted morphological and functional differentiation of non-malignant mammary epithelial cells by interfering with alveolar morphogenesis and functional differentiation (Parrinello et al., 2005). Irradiation induces senescent cells in salivary gland-derived organoids, which secrete SASP factors (Il-6, Mcp1, Cxcl1, and Gdnf) that compromise stem-cell self-renewal and function. Clearance of senescent cells with senolytic drug ABT263 improves stem-cell self-renewal by increasing the number of aquaporin 5+ acinar cells and saliva production in vivo (Peng et al., 2020). The inability of salivary-gland stem cells to proliferate when close to the senescent cells may exacerbate radiation-induced normal tissue damage. It is thought-provoking to consider that eliminating senescent cells from treated tumours may be a safe therapeutic strategy that can be used to improve the therapeutic ratio, and that patient-specific senescent cells may be developed into potent cell therapies to harness a systemic anti-tumour immune response. However, it is necessary to perform further studies to apply these insights to identify the therapeutic window of anti-senolytics and the use of senescent cancer-cell vaccines.
Marc Vooijs and Lorena Giuranno
Department of Radiation Oncology
GROW School of Oncology and Reproduction
Maastricht University Medical School
MUMC+
Maastricht, The Netherlands
marc.vooijs@maastrichtuniversity.nl
Bibliography
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Xiaohong Peng, Yi Wu, Uilke Brouwer, Thijmen van Vliet, Boshi Wang, Marco Demaria, Lara Barazzuol, and Rob P. Coppes. 2020. Cellular Senescence Contributes to Radiation-Induced Hyposalivation by Affecting the Stem/Progenitor Cell Niche. Cell Death and Disease 11(10). doi: 10.1038/s41419-020-03074-9.