Different sensitivities of senescent breast cancer cells to immune cell‐mediated cytotoxicity

Inao, Touko; Kotani, Hitoshi; Iida, Yuichi; Kartika, Irna Diyana; Okimoto, Tamio; Tanino, Ryosuke; Shiba, Eiichi; Harada, Mamoru

doi:10.1111/cas.14116

Cited by 29 publications

(36 citation statements)

References 42 publications

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“…Before the assays, T cells were in vitro expanded after 2 days of culture in anti–CD3 antibody‐coated wells with 300 U/mL IL‐2 and then with IL‐2 alone for 7‐10 days. Although the in vitro expanded CAR‐T cells were unexpectedly positive for CD4, 14 we performed experiments using these activated T cells. The percentages of apoptotic cancer cells were examined by flow cytometry by gating CD45‐negative cells.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, they exerted higher levels of cytotoxicity against PEM‐treated PC9 and A549 cells than against untreated cancer cells. In terms of the underlying mechanism, we recently reported that these activated CD4 + T cells showed enhanced cytotoxicity against doxorubicin‐treated human breast cancer cells partially through the tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)/death receptor system 14 . This apoptosis‐inducing system may be involved in augmenting the sensitivity of PEM‐treated NSCLC cells to cytotoxic immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Pemetrexed sensitizes human lung cancer cells to cytotoxic immune cells

et al. 2020

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Pemetrexed (PEM) is a useful drug that can be combined with immune checkpoint blockade therapy for treatment of patients with advanced non–small‐cell lung cancer (NSCLC). However, its effects on anti–cancer immunity, especially the sensitivity of NSCLC cells to cytotoxic immune cells, have not been fully investigated. In this study, we examined the effects of PEM on the sensitivity of human NSCLC cells to two different types of cytotoxic immune cells. Pre‐treatment with PEM increased the sensitivity of two NSCLC cell lines, PC9 and A549, to activated T cells and natural killer (NK) cells, and decreased the expression of anti–apoptotic proteins, including XIAP and Mcl‐1. In addition, PEM treatment increased the cell surface expression of programmed death‐ligand 1 (PD‐L1) on PC9 cells. PEM‐induced upregulation of PD‐L1 on PC9 cells was at least partially ascribed to activation of ERK and the NFκB pathway. In contrast, PEM treatment increased the expression of UL16‐binding proteins (ULBP), ligands for the NKG2D NK receptor, on PC9 and A549 cells, as well as the induction of senescence. Although the addition of anti–programmed cell death 1 antibody showed no effect on the sensitivity of PEM‐treated PC9 and A549 cells to activated T cells, that of anti–NKG2D antibody decreased the enhanced sensitivity of PEM‐treated A549 cells to NK cells. These results indicate that PEM can effectively sensitize human NSCLC cells to cytotoxic immune cells while modulating the expression of immune‐regulatory molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pemetrexed sensitizes human lung cancer cells to cytotoxic immune cells

et al. 2020

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“…These events allow the functional trans-presentation of IL-15 to neighboring NK cells leading to NK cell recognition and cytotoxicity [ 194 ]. Moreover, additional NK mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) are activated after chemotherapy to eliminate senescent breast cancer cells, where doxorubicin enhances senescence through SASP secretion leading to a perforin-dependent increase in ADCC by NK cells [ 195 ].…”

Section: Clinical Relevance Of Senescence In Immunotherapy: a Balamentioning

confidence: 99%

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

Battram

Bachiller

Martín-Antonio

2020

IJMS

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Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence.

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“…Those results were partially confirmed by Huun and co-workers in MCF-7 cells as well as via other authors (in vitro and in vivo models) since only concomitant inactivation of P53 and RB genes led to a decrease of the senescent cells numbers [ 26 , 27 , 28 , 29 ]. Studies on p53-mutated MDA-MB-231 and BT-549 cells revealed that doxorubicin-induced senescence led to an increased expression level of p 21 and p16, respectively [ 25 , 30 ].…”

Section: Senescence and Anticancer Strategymentioning

confidence: 99%

“…Matrix enzymes can remodel the microenvironment to promote cancer initiation and development. Some SASP proteins, e.g., cytokines and THBS1, act in maintenance of senescence [ 23 , 29 , 30 , 86 , 94 ].…”

Section: Senescence Induction As a New Anticancer Strategymentioning

confidence: 99%

The Premature Senescence in Breast Cancer Treatment Strategy

Milczarek

2020

Cancers

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Cellular senescence is a permanent blockade of cell proliferation. In response to therapy-induced stress, cancer cells undergo apoptosis or premature senescence. In apoptosis-resistant cancer cells or at lower doses of anticancer drugs, therapy-induced stress leads to premature senescence. The role of this senescence in cancer treatment is discussable. First of all, the senescent cells lose the ability to proliferate, migrate, and invade. In addition, the senescent cells secrete a set of proteins (inflammatory cytokines, chemokines, growth factors) known as the senescence-associated secretory phenotype (SASP), which influences non-senescent normal cells and non-senescent cancer cells in the tumor microenvironment and triggers tumor promotion and recurrence. Recently, many studies have examined senescence induction through breast cancer therapy and potentially using this phenomenon to treat this cancer. This review summarizes the recent in vitro, in vivo, and clinical studies investigating senescence in breast cancer treatments. Senescence inductors, senolytics, as well as their action mechanism are discussed herein. Potential SASP-modulating treatment strategies are also described.

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Different sensitivities of senescent breast cancer cells to immune cell‐mediated cytotoxicity

Cited by 29 publications

References 42 publications

Pemetrexed sensitizes human lung cancer cells to cytotoxic immune cells

Pemetrexed sensitizes human lung cancer cells to cytotoxic immune cells

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

The Premature Senescence in Breast Cancer Treatment Strategy

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