Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment

Vilgelm, Anna E.; Johnson, Christopher Andrew; Prasad, Nripesh; Yang, Jinming; Chen, Sheau-Chiann; Ayers, Gregory D.; Pawlikowski, Jeff S.; Raman, Dayanidhi; Sosman, Jeffrey A.; Kelley, Mark C.; Ecsedy, Jeffrey; Shyr, Yu; Levy, Shawn; Richmond, Ann

doi:10.1093/jnci/djv406

Cited by 67 publications

(76 citation statements)

References 43 publications

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“…It was demonstrated that Aurora A inhibition elicited the recruitment of CD8 þ T cells to the tumor microenvironment via release of the CCL5 cytokine from tumor cells that underwent senescence in a melanoma tumor model (26). Therefore, T cells that are enriched in mammary tumors can also be recruited by senescent tumor cells upon alisertib administration.…”

Section: The Immunogenic Tumor Microenvironment Is Reshaped Prior To mentioning

confidence: 99%

“…Increasing studies demonstrated that besides killing tumor cells directly, chemotherapeutic drugs can also inhibit tumor growth via enhancing antitumor immunity through different mechanisms (24,25). Likewise, alisertib administration has been reported to enhance the recruitment of tumor-infiltrating leukocytes via inducing senescence of melanoma cells (26). However, the direct effect of Aurora A inhibition on the immune microenvironment of breast cancer is barely known.…”

Section: Introductionmentioning

confidence: 99%

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Aurora A Inhibition Eliminates Myeloid Cell–Mediated Immunosuppression and Enhances the Efficacy of Anti–PD-L1 Therapy in Breast Cancer

Yin¹,

Zhao

Guo³

et al. 2019

Cancer Research

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The Aurora A inhibitor alisertib shows encouraging activities in clinical trials against advanced breast cancer. However, it remains unclear whether and how the inflammatory microenvironment is involved in its efficacy. Here, we demonstrated that inhibition of Aurora A directly reshaped the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anticancer T lymphocytes, which established a tumor-suppressive microenvironment and significantly contributed to the regression of murine mammary tumors. Mechanistically, alisertib treatment triggered apoptosis in myeloid-derived suppressor cells (MDSC) and macrophages, resulting in their elimination from tumors. Furthermore, alisertib treatment disrupted the immunosuppressive functions of MDSC by inhibiting Stat3-mediated ROS production. These alterations led to significant increases of active CD8 þ and CD4 þ T lymphocytes, which efficiently inhibited the proliferation of tumor cells. Intriguingly, alisertib combined with PD-L1 blockade showed synergistic efficacy in the treatment of mammary tumors. These results detail the effects of Aurora A inhibition on the immune microenvironment and provide a novel chemo-immunotherapy strategy for advanced breast cancers.Significance: These findings show that inhibition of Aurora A facilitates an anticancer immune microenvironment, which can suppress tumor progression and enhance anti-PD-L1 therapy in breast cancer.

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Section: The Immunogenic Tumor Microenvironment Is Reshaped Prior To mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aurora A Inhibition Eliminates Myeloid Cell–Mediated Immunosuppression and Enhances the Efficacy of Anti–PD-L1 Therapy in Breast Cancer

Yin¹,

Zhao

Guo³

et al. 2019

Cancer Research

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“…Cell senescence is a special active state characterized by irreversible growth arrest and modified immunostimulatory cytokine secretion . Cellular senescence is caused not only by telomere shortening after multiple replications, but also when cells experience environmental insults (stress‐induced senescence) .…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Cell senescence is a special active state characterized by irreversible growth arrest and modified immunostimulatory cytokine secretion. [12][13][14][15] Cellular senescence is caused not only by telomere shortening after multiple replications, but also when cells experience environmental insults (stress-induced senescence). 2 Senescent cells typically extensively alter their cytokine secretion profiles, resulting in development of the senescence-associated secretory phenotype (SASP).…”

Section: Introductionmentioning

confidence: 99%

Senescent cells re‐engineered to express soluble programmed death receptor‐1 for inhibiting programmed death receptor‐1/programmed death ligand‐1 as a vaccination approach against breast cancer

Feng

et al. 2018

Cancer Science

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Various types of vaccines have been proposed as approaches for prevention or delay of the onset of cancer by boosting the endogenous immune system. We previously developed a senescent‐cell‐based vaccine, induced by radiation and veliparib, as a preventive and therapeutic tool against triple‐negative breast cancer. However, the programmed death receptor‐1/programmed death ligand‐1 (PD‐1/PD‐L1) pathway was found to play an important role in vaccine failure. Hence, we further developed soluble programmed death receptor‐1 (sPD1)‐expressing senescent cells to overcome PD‐L1/PD‐1‐mediated immune suppression while vaccinating to promote dendritic cell (DC) maturity, thereby amplifying T‐cell activation. In the present study, sPD1‐expressing senescent cells showed a particularly active status characterized by growth arrest and modified immunostimulatory cytokine secretion in vitro. As expected, sPD1‐expressing senescent tumor cell vaccine (STCV/sPD‐1) treatment attracted more mature DC and fewer exhausted‐PD1+ T cells in vivo. During the course of the vaccine studies, we observed greater safety and efficacy for STCV/sPD‐1 than for control treatments. STCV/sPD‐1 pre‐injections provided complete protection from 4T1 tumor challenge in mice. Additionally, the in vivo therapeutic study of mice with s.c. 4T1 tumor showed that STCV/sPD‐1 vaccination delayed tumorigenesis and suppressed tumor progression at early stages. These results showed that STCV/sPD‐1 effectively induced a strong antitumor immune response against cancer and suggested that it might be a potential strategy for TNBC prevention.

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“…Furthermore, a large study of 1000 PDXs reported remarkable reproducibility and the clinical translatability of this preclinical model, which makes it invaluable for evaluation of novel treatment modalities (Gao et al., ). We have extensively implemented PDXs to test promising therapeutic regimens, including combination of mitotic inhibitors with MDM2 antagonist, as well as to study the outcome of therapy‐induced senescence (Vilgelm et al., , ). However, due to the expense, timing, and complexity of the assays, one can envision a series of preclinical studies linked to clinical trials to demonstrate whether each individual PDX can consistently predict response to second‐line therapy.…”

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confidence: 99%

Using avatars to win the fight over BRAF inhibitor resistance

Vilgelm¹,

Richmond²

2016

Pigment Cell Melanoma Res

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Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment

Abstract: Senescent melanoma cells secret CCL5, which promotes recruitment of TILs. Combining TIS with immunotherapy that enhances tumor cell killing by TILs is a promising novel approach to improve melanoma outcomes.

Cited by 67 publications

References 43 publications

Aurora A Inhibition Eliminates Myeloid Cell–Mediated Immunosuppression and Enhances the Efficacy of Anti–PD-L1 Therapy in Breast Cancer

Aurora A Inhibition Eliminates Myeloid Cell–Mediated Immunosuppression and Enhances the Efficacy of Anti–PD-L1 Therapy in Breast Cancer

Senescent cells re‐engineered to express soluble programmed death receptor‐1 for inhibiting programmed death receptor‐1/programmed death ligand‐1 as a vaccination approach against breast cancer

Using avatars to win the fight over BRAF inhibitor resistance

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