Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells

Abstract

BackgroundImmune tolerance contributes to resistance to conventional cancer therapies such as radiation. Radiotherapy induces immunogenic cell death, releasing a burst of tumor antigens, but this appears insufficient to stimulate an effective antitumor immune response. Radiation also increases infiltration of cytotoxic T lymphocytes (CTLs), but their effector function is short lived. Although CTL exhaustion may be at fault, combining immune checkpoint blockade with radiation is insufficient to restore CTL function in most patients. An alternative model is that antigen presentation is the limiting factor, suggesting a defect in dendritic cell (DC) function.MethodsBuilding on our prior work showing that cancer cells treated with radiation in the presence of the poly(ADP-ribose) polymerase-1 inhibitor veliparib undergo immunogenic senescence, we reexamined senescent cells (SnCs) as preventative or therapeutic cancer vaccines. SnCs formed in vitro were cocultured with splenocytes and evaluated by scRNA-seq to examine immunogenicity. Immature bone-marrow-derived DCs cocultured with SnCs were examined for maturation and activation by flow cytometry and T cell proliferation assays. Viable SnCs or SnC-activated DCs were injected subcutaneously, and vaccine effects were evaluated by analysis of immune response, prevention of tumor engraftment, regression of established tumors and/or potentiation of immunotherapy or radiotherapy.ResultsMurine CT26 colon carcinoma or 4T1 mammary carcinoma cells treated with radiation and veliparib form SnCs that promote DC maturation and activation in vitro, leading to efficient, STING-dependent CTL priming. Injecting mice with SnCs induces antigen-specific CTLs and confers protection from tumor engraftment. Injecting immunogenic SnCs into tumor-bearing mice increases inflammation with activated CTLs, suppresses tumor growth, potentiates checkpoint blockade, enhances radiotherapy and blocks colonization by disseminated tumor cells. Addressing the concern that reinjecting tumor cells into patients may be impractical, DCs activated with SnCs in vitro were similarly effective to SnCs in suppressing established tumors and blocking metastases.ConclusionsTherapeutic vaccines based on senescent tumor cells and/or SnC-activated DCs have the potential to improve genotoxic and immune therapies and limit recurrence or metastasis.

T-cell immunity against senescence: potential role and perspectives

“…Many anticancer therapies have been shown to induce tumor cell senescence, which promotes the recruitment and activation of CD4 + and CD8 + lymphocytes and enhances antitumor protection ( 64 , 65 ). Interestingly, immunization with derivatives of senescent tumor cells induces a stronger and more effective antitumor immune response than immunization with derivatives of tumor cells after immune-mediated tumor cell death ( 48 , 63 , 66 ). In other words, induction of senescence makes it possible to solve the problem of low immunogenicity of autologous tumor antigens.…”

“…However, the formation of an adequate immune response to non-LTR epitopes does not occur due to the inhibitory influence of the tumor microenvironment and the dualistic role of senescent cells in tumors ( 82 , 85 ). It can be assumed that the use of nanovesicles of tumor cells with induced senescence as a vaccine creates an effective T-cell immune response against epitopes of non-LTR elements since its formation occurs outside the inhibitory tumor microenvironment ( 48 , 56 , 57 ). Such antitumor immune response is probably produced not by tumor neoantigens but by epitopes of retrotransposons whose activity is increased in the tumor.…”

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

“…Tumor-derived DNA or cGAMP is internalized and processed by DCs that have infiltrated tumors; subsequently the cGAS-STING pathway is activated and the production of IFN-α/β is induced. This process drives DC differentiation and maturation, and concurrently enhances major histocompatibility complex class I (MHC-I) expression and facilitates DC-mediated cytotoxic T lymphocyte (CTL) anti-tumor responses 43 . Furthermore, the cGAS-STING pathway amplifies the expression of co-stimulatory molecules (e.g., CD40, CD80, and CD86) on DCs while simultaneously decreasing the expression of inhibitory molecules, such as programmed death-ligand 1 (PD-L1) 44 .…”

“…In murine models, treatment of CT26 colorectal cancer or 4T1 breast cancer cells with radiation has been demonstrated to initiate effective STING-dependent CTL responses 43 . Platinum-based chemotherapy has similarly been shown to activate STING and increase expression of MHC-I in cancer cells.…”

Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment

“…But, on the other hand, the induction of senescence during cancer treatment could be used as a potential mechanism to induce immune reaction against cancer cells. Recently, Liu et al 72 highlighted the fact that senescent cancer cells could be used as cancer vaccine by activating the antitumor immunity. Indeed, they showed that dendritic cells are activated in vitro in co-culture with senescent cancer cells.…”