Abstract SoA2-01: Cellular senescence: The senescence-associated secretory phenotype (SASP) and immunity

Abstract

Abstract Cellular senescence is a stress-induced program following aberrant oncogene activation or administration of cancer therapies, including chemotherapeutic agents and CDK4/6 inhibitors commonly used for treating advanced breast cancers, that results in the proliferative arrest of damaged cells and induction of the senescence associated secretory phenotype (SASP). The SASP involves secretion of inflammatory cytokines and chemokines and upregulation of immunomodulatory cell surface molecules on senescent cells that can promote their clearance by the immune system and tumor resolution. However, if left unchecked, the chronic SASP can also lead to immune suppression and further tissue damage that drives tumor dissemination and metastasis. Here we will discuss our efforts to understand how the SASP can promote anti-tumor immunity and immunotherapy activity in some cancer contexts yet in others immune suppression and tumor promotion. Our findings in other solid tumor contexts demonstrate that the tissue microenvironment has a profound impact of the type of SASP program activated and SASP-mediated immune responses produced and suggest further therapeutic interventions to remodel the SASP for immune control of cancer. Moreover, our results in other hormone-driven cancers suggest that CDK inhibitor and chemotherapy regimens produce different SASPs and resulting effects on myeloid cell and lymphocyte phenotypes that could explain their varying effects on anti-tumor immunity and treatment outcomes. Collectively these findings have important implications for breast cancer treatment and pave the path for rationale combination therapies with senescence-inducing agents to achieve immune control in breast and other immunologically “cold” solid tumor malignancies that are generally unresponsive to current immunotherapy regimens. Citation Format: M. Ruscetti. Cellular senescence: The senescence-associated secretory phenotype (SASP) and immunity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr SoA2-01.