Aging cancer cells can activate immune cells and promote anti-tumor immunity

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Aging cancer cells can activate immune cells and promote anti-tumor immunity

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The latest research from the Karolinska Institutet in Sweden: Aging cancer cells can activate immune cells and promote anti-tumor immunity.

Introduction :

The Federico Pietrocola research group from the Karolinska Institutet in Sweden and Manuel Serrano from the Barcelona Institute of Science and Technology, Spain, published the latest research results in Cancer Discovery, revealing that aging cancer cells can be used to establish efficient, protective Sexual CD8 T cell-dependent antitumor immunity.

Cellular senescence is a stress response designed to eliminate unwanted, damaged or abnormal cells. This response includes a steady proliferative arrest and exuberant secretion of pro-inflammatory substances (also known as senescence-associated secretory phenotype, SASP).

Through SASP, senescent cells can recruit immune cells to promote their own immune clearance and restore tissue homeostasis.

Cancer cells are often exposed to a variety of stressors known to trigger senescence, including oncogenic signaling, replication stress, hypoxia, reactive oxygen species, nutrient deprivation, and cytokines present in the tumor microenvironment, such as TGFβ; in addition, various This anticancer therapy can also induce senescence in cancer cells.

As a result, tumors before and after treatment often contain different proportions of senescent cells—which has been recognized as a “hallmark of cancer.”

Senescent cancer cells do not promote tumor growth by themselves due to their low proliferative ability; however, senescent cancer cells can alter the tumor microenvironment through SASP.

SASPs produced by senescent cells within tumors have complex and often opposite effects on tumor behavior—often dependent on multiple factors that reflect in part cancer intrinsic heterogeneity and response to cancer therapy. Notably, SASP of tumor cells can recruit and activate CD4 and CD8 T cells, triggering antitumor protection.

On February 6, 2023, Federico Pietrocola’s research group from Karolinska Institutet, Sweden, and Manuel Serrano from the Barcelona Institute of Science and Technology, Spain published a paper entitled “Cellular Senescence Is Immunogenicity” in Cancer Discovery (IF:38.3). and Promotes Antitumor Immunity”, revealing that senescent cancer cells can be used to establish efficient and protective CD8 T cell-dependent anti-tumor immunity.

https://aacrjournals.org/cancerdiscovery/article/13/2/410/716304/Cellular-Senescence-Is-Immunogenic-and-Promotes

The research team performed a proteomic screen on plasma membrane-enriched fractions from senescent cells to identify proteins with potential immunomodulatory activity on senescent cells.

In total, they analyzed four different cell types and tested seven different aging conditions.

Successful induction of senescent cells was confirmed by monitoring senescence-associated β-galactosidase (SAβG) activity and mRNA expression of at least one senescence-associated gene.

ene Ontology (GO) analysis of genes encoding genes that were significantly increased in four or more aging conditions compared to corresponding non-aging controls found that “antigen processing and antigen presentation by MHC class I” was the most abundant category.

These experimental results demonstrate that senescent cancer cells upregulate MHC-I antigen presentation.

Given this, the researchers wondered whether senescent cells could induce an antigen-dependent immune response in vivo; the study therefore included non-cancer cells — which are less immunogenic than cancer cells.

Compared with splenocytes from ova-immunized mice exposed to SIINFEKL, splenocytes from senMEF-immunized mice responded strongly after ex vivo re-exposure to senMEF, producing many spots on basal activity.

Interestingly, splenocytes from senMEF-immunized mice also responded to non-senescent MEFs in vitro—although not as strongly as senMEF.

As additional evidence, both CD69 and CD25 expression were elevated in CD8 T cells from senMEF-immunized animals when exposed to senMEF in vitro; this activation was also detectable when CD8 T cells were exposed to non-senescent MEFs, But to a lesser extent.

Collectively, the experimental results suggest that senescent cells can activate CD8 T cells.

The results showed that senescent cancer cells are highly immunogenic due to the activation of IFN signaling, efficient antigen transfer and activation of APCs, upregulated antigen presentation, and altered immune peptide structure.

MHC-I downregulation remains the main mechanism by which cancer cells evade CD8 T cell killing, and senescence-associated MHC-I upregulation may be an important strategy to overcome immune evasion associated with MHC-I downregulation.

The study also suggests the possibility of improving anticancer vaccination strategies based on senescent cancer cells.

Furthermore, senescent cancer cells can also be used to produce and improve DC vaccines, given their ability to deliver antigens and activate DC cells.

Reference:

https://aacrjournals.org/cancerdiscovery/article/13/2/410/716304/Cellular-Senescence-Is-Immunogenic-and-Promotes

Aging cancer cells can activate immune cells and promote anti-tumor immunity

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