The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2.

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.

Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity.

Cellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DC) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of IFN signaling, enhanced MHC class I machinery, and presentation of senescence-associated self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong antitumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent antitumor immune responses. SIGNIFICANCE: Our study shows that senescent cells are endowed with a high immunogenic potential-superior to the gold standard of immunogenic cell death. We harness these properties of senescent cells to trigger efficient and protective CD8-dependent antitumor immune responses. See related article by Chen et al., p. 432. This article is highlighted in the In This Issue feature, p. 247.

Cellular senescence enhances adaptive anticancer immunosurveillance.

Cancer therapy often induces senescence in some cancer cells. Senescent cells, due to their profoundly altered biology, may conceivably interact with the adaptive immune system in novel ways that may boost cancer immunosurveillance, triggering the clearance of both senescent and non-senescent neoplastic cells. In this regard, we have recently reported that senescent cancer cells exhibit potent antigenicity and adjuvanticity and can elicit strong CD8+ T cell-dependent anticancer effects when used as vaccination agents.

The lysosomal proteome of senescent cells contributes to the senescence secretome.

Senescent cells accumulate in tissues over time, favoring the onset and progression of multiple age-related diseases. Senescent cells present a remarkable increase in lysosomal mass and elevated autophagic activity. Here, we report that two main autophagic pathways macroautophagy (MA) and chaperone-mediated autophagy (CMA) are constitutively upregulated in senescent cells. Proteomic analyses of the subpopulations of lysosomes preferentially engaged in each of these types of autophagy revealed profound quantitative and qualitative changes in senescent cells, affecting both lysosomal resident proteins and cargo proteins delivered to lysosomes for degradation. These studies have led us to identify resident lysosomal proteins that are highly augmented in senescent cells and can be used as novel markers of senescence, such as arylsulfatase ARSA. The abundant secretome of senescent cells, known as SASP, is considered their main pathological mediator; however, little is known about the mechanisms of SASP secretion. Some secretory cells, including melanocytes, use the small GTPase RAB27A to perform lysosomal secretion. We found that this process is exacerbated in the case of senescent melanoma cells, as revealed by the exposure of lysosomal membrane integral proteins LAMP1 and LAMP2 in their plasma membrane. Interestingly, a subset of SASP components, including cytokines CCL2, CCL3, CXCL12, cathepsin CTSD, or the protease inhibitor SERPINE1, are secreted in a RAB27A-dependent manner in senescent melanoma cells. Finally, proteins previously identified as plasma biomarkers of aging are highly enriched in the lysosomes of senescent cells, including CTSD. We conclude that the lysosomal proteome of senescent cells is profoundly reconfigured, and that some senescent cells can be highly active in lysosomal exocytosis.

MRGBP, a member of the NuA4 complex, inhibits DNA double-strand break repair.

The repair of DNA breaks takes place in the context of chromatin and thus involves the activity of chromatin remodelers. The nucleosome acetyltransferase of H4 (NuA4) remodeler complex enables DNA break repair by relaxing flanking chromatin. Here, we show that MRG domain binding protein (MRGBP), a member of this complex, acts as a general inhibitor of DNA double-strand break repair. Upon its downregulation, repair is generally increased. This is particularly evident for the stimulation of early events of homologous recombination. Thus, MRGBP has an opposing role to the main catalytic subunits of the NuA4 complex. Our data suggest that MRGBP acts by limiting the activity of this complex in DNA repair, specifically by narrowing the extent of DNA-end resection.

La aceptabilidad jurídica de Ia técnica de gestación de vida humana por sustitución de vientre / No disponible

En el presente artículo se expondrán algunos de los argumentos que se esgrimen sobre la aceptabilidad jurídica de la técnica de gestación de vida humana por sustitución de vientre, comenzando por establecer las múltiples denominaciones que de ella se han realizado y que han conllevado a conocerla con los nombres de alquiler de vientre, maternidad subrogada o maternidad sustituta. Posteriormente se determinarán los aspectos legales que conlleva el tránsito de la técnica a su realización a través de contratos, precisando de esta manera los elementos esenciales (capacidad, consentimiento, causa y objeto licito), el contenido y la posible forma de los contratos de gestación de vida humana por sustitución de vientre (AU)

This article will present some of the arguments that have been exposed about the legal acceptability in the technique of gestation of human life by surrogacy, beginning for establish the multiple denominations that have been realized and which make know this technique as: surrogacy, surrogate motherhood or substitute motherhood. Then it will determine the legal aspects involved in the transit of this technique to its accomplishment through contracts, thereby specifying the essential elements (capacity, consent, cause and lawful purpose), the content and the possible manner of gestation human life contracts by surrogacy (AU)

[Not Available]. / La aceptabilidad jurídica de la técnica de gestación de vida humana por sustitución de vientre.

This article will present some of the arguments that have been exposed about the legal acceptability in the technique of gestation of human life by surrogacy, beginning for establish the multiple denominations that have been realized and which make know this technique as: surrogacy, surrogate motherhood or substitute motherhood. Then it will determine the legal aspects involved in the transit of this technique to its accomplishment through contracts, thereby specifying the essential elements (capacity, consent, cause and lawful purpose), the content and the possible manner of gestation human life contracts by surrogacy.