Senescence and the tumor-immune landscape: Implications for cancer immunotherapy

Abstract

Cancer therapies, including conventional chemotherapy, radiation, and molecularly targeted agents, can lead to tumor eradication through a variety of mechanisms. In addition to their effects on tumor cell growth and survival, these regimens can also influence the surrounding tumor-immune microenvironment in ways that ultimately impact therapy responses. A unique biological outcome of cancer therapy is induction of cellular senescence. Senescence is a damage-induced stress program that leads to both the durable arrest of tumor cells and remodeling the tumor-immune microenvironment through activation of a collection pleiotropic cytokines, chemokines, growth factors, and proteinases known as the senescence-associated secretory phenotype (SASP). Depending on the cancer context and the mechanism of action of the therapy, the SASP produced following therapy-induced senescence (TIS) can promote anti-tumor immunity that enhances therapeutic efficacy, or alternatively chronic inflammation that leads to therapy failure and tumor relapse. Thus, a deeper understanding of the mechanisms regulating the SASP and components necessary for robust anti-tumor immune surveillance in different cancer and therapy contexts are key to harnessing senescence for tumor control. Here we draw a roadmap to modulate TIS and its immune-stimulating features for cancer immunotherapy.

Keywords: Cellular senescence; Immunotherapy; Senescence-associated secretory phenotype; Senotherapeutics; Tumor microenvironment.

Fig. 1.. Overview of senescence regulation of tumor-immune interactions following cancer therapy and potential senotherapeutic interventions.

(1) Certain cancer therapies, including radiation, chemotherapy, and targeted therapies such as CDK4/6 and AURKA inhibitors, can cause cellular senescence through induction of DNA damage, a prolonged DDR orchestrated by ATM/ATR, and/or downstream activation of p53 and RB-regulated pathways, leading to cell cycle arrest. (2) RB and epigenetic modifiers lead to chromatin changes in senescent cells that repress accessibility at cell cycle genes but increase open chromatin and binding of BRD4 to enhancer regions at SASP gene loci. (3) RB, ATM/ATR, p38MAPK, GATA4, and NOTCH1, as well as the cGAS-STING pathway that is activated by binding cytosolic double-stranded DNA, also interact with and activate TFs such as NF-κB, C/EBPβ, and STATs that bind to SASP gene promoters and promote their transcription. (4) Depending on the mechanism of action of the therapy, the cancer and cell type it acts on, and the upstream epigenetic and transcriptional regulators activated, the composition of the SASP can be incredibly heterogeneous, comprising pro-inflammatory, anti-inflammatory, and angiogenic factors, as well as lipids, MMPs, and other growth factors. (5) Many of these SASP factors highlighted have been shown to modulate the immune system and the vasculature in both tumor suppressive and tumor-promoting ways. In addition, the upregulation of cell surface proteins on senescent cells as part of the SASP can allow them to be recognized by (MHC-I, NK ligands) or alternatively evade (HLA-E, PD-L1) the immune system. (6) The secretome and surfaceome of senescent tumor cells can be leveraged for immunotherapy, including ICB therapies to block PD-L1 and HLA-E, CAR-T cells and antibodies engineered to bind senescence-related surface proteins, and neutralizing antibodies to target immune suppressive SASP factors, such as IL-6, IL-8, and TGF-β, and their receptors. (7) Similarly, senomorphic agents targeting SASP transcriptional regulation, including inhibitors of BRD4 (JQ1), STAT3 (Ruxolitinib), NF-κB (BAY 11–7082, Metformin), and p38MAPK (SB203580) can be used to modulate specific SASP programs. (8) Alternatively, senolytic agents targeting pro-survival and anti-apoptotic pathways in senescent cells such as BCL-2 (Navitoclax), MDM2 (UBX101), and PI3K signaling (Dasatinib + Quercetin) can be used to kill deleterious senescent tumor cells. AURKA, Aurora Kinase A; CAR-T, chimeric antigen receptor (CAR) T cell; DDR, DNA damage response; ICB, immune checkpoint blockade; mAb, monoclonal antibodies; MMP, matrix metalloproteinases; NCID, NOTCH intracellular domain; Pol II, RNA polymerase II; SASP, senescence-associated secretory phenotype; TF, transcription factor.

Fig. 2.. Pipeline to identify immune-stimulatory senescence-inducing cancer therapies and SASP biomarkers for the clinic.

(1) In vitro genetic and pharmacological screens can be performed on genetically-defined cancer cell lines engineered with fluorescent senescence and SASP reporters to identify new senescence-inducing therapies for defined cancer contexts. These candidate senescence-inducing therapies can then be tested in immunocompetent mouse models harboring transplanted or autochthonous tumors to evaluate their anti-tumor efficacy. (2) The impact of therapy-induced senescence on tumor-immune interactions can be assessed using in vitro co-culture systems and in vivo tumor mouse models with intact TMEs. (3) SASP factors and regulators that functionally impact tumor-immune interactions can then be identified by inducing or suppressing their expression genetically or pharmacologically through the pipeline in (1). (4) The immunomodulatory effects of senescence-inducing therapies and SASP biomarkers of immune and tumor responses can be validated in tissue and liquid biopsies from cancer patients treated in the clinic. mAb, monoclonal antibodies; TME, tumor microenvironment.