Senescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity

Abstract

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent liver cancer model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels the cell surface proteome to alter how tumor cells sense environmental factors, as exemplified by Type II interferon (IFN-y). Compared to proliferating cells, senescent cells upregulate the IFN-y receptor, become hypersensitized to microenvironmental IFN-y, and more robustly induce the antigen presenting machinery—-effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFN-y sensing in senescent cells blunts their immune-mediated clearance without disabling the senescence state or its characteristic secretory program. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance.

Therapy-induced senescence upregulates antigen presentation machinery and triggers anti-tumor immunity in Acute Myeloid Leukemia

“…By undertaking several state-of-the-art immunological assays, we reported that “Senescence High” AML blasts undergoing TIS elicited a strong CD8 + T cell activation, likely due to HLA class I upregulation, and led to leukemia eradication in line with two recent reports showing that senescence triggers CD8 + T cells anti-tumor immunity 15,16 , supporting the idea that immune recognition of senescent cells by CD8 + T cells is conserved even in hematological cancers. HLA class II molecules play a central role in the control of adaptive immune responses through the activation of CD4 + T cells 31 .…”

“…HLA class II molecules play a central role in the control of adaptive immune responses through the activation of CD4 + T cells 31 . We discovered that HLA class II up-regulation in senescent AML blasts correlated with increased CD4 + T cell immune activation, as determined by enhanced proliferation, immunological synapsis formation, and eradication of TIS cells, an aspect not considered in studies performed so far in the context of immunogenicity of solid tumors 15,16 . The involvement of CD4 + T cells in AML eradication is in line with the reported role of this T cell subset in mediating immune recognition of post-allogeneic Hematopoietic Cells Transplant (allo-HCT) relapses upon reactivation of HLA class II expression 30 .…”

“…Specifically, senescent cells were shown to upregulate activating ligands on their surface and favor the recruitment and activation of several cell types of the innate immune system, including macrophages 11,12 , natural killer 13 , dendritic and invariant natural killer T cells 14 , thus contributing to effective senescence immune-surveillance in relevant mouse models of replicative and oncogene-induced senescence. When activated, cells of the innate immune system may in turn initiate and potentiate adaptive immunity against senescent cells, unleashing mainly cytotoxic CD8 + T cell responses 15,16 , while the contribution of the CD4 + T cells to senescence eradication was, to date, only limited to models of premalignant senescent hepatocytes upon MHC class II upregulation 17 .…”

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

“… 43 An added benefit of greater SnC immunogenicity is that it may potentiate rapid immune clearance and limit SnC persistence, reducing the deleterious effects of the SASP in the tumor microenvironment. Taken together with this work, prior studies 13 35 along with exciting new results published while this paper was under consideration 44 45 provide strong evidence that SnCs can be immunogenic, inducing a cytotoxic T cell response with potential to not only clear SnCs but also prevent or eliminate tumors.…”

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells

“…This phenomenon is characterized as the senescence associated secretory phenotype (SASP) and has been observed in response to multiple, distinct senescence inducers (19)(20)(21). Numerous lines of investigation have now demonstrated that the milieu of cytokines secreted by senescent fibroblasts can create a permissive environment for cancer cells (22)(23)(24)(25)(26). These data have motivated significant interest in the use of senolytic drugs, which specifically kill senescent cells, as a novel therapeutic strategy in multiple cancer types (27)(28)(29).…”