Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis

Janneh, Alhaji H.; Kassir, Mohamed Faisal; Atilgan, F. Cansu; Lee, Han Gyul; Sheridan, Megan A.; Oleinik, Natalia; Szulc, Zdzisław M.; Voelkel‐Johnson, Christina; Nguyen, Hung; Li, Hong; Peterson, Yuri K.; Marangoni, Elisabetta; Saatçi, Özge; Şahin, Özgür; Lilly, Michael; Atkinson, Carl; Tomlinson, Stephen; Mehrotra, Shikhar; Öğretmen, Besim

doi:10.1016/j.celrep.2022.111742

Cited by 9 publications

(14 citation statements)

References 66 publications

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“…It is possible a small number of cancer-specific memory clones are sufficient to suppress recurrence. Additionally, S1P metabolism promotes metastasis via activating cell-autonomous signaling pathways such as the C3 complement pathway 75 or PAK1/LIMK1/Cofilin1 pathway 76 in cancer cells, which adds another caveat of using systemic S1P inhibition.…”

Section: Discussionmentioning

confidence: 99%

Cancer immunotherapy response persists after lymph node resection

Zhou,

Menzel,

Baish

et al. 2023

Preprint

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Due to the critical role of lymph nodes (LNs) in the initiation and maintenance of adaptive immune responses, it is unclear whether surgical removal or ablative radiation therapy of LNs should be performed in patients with metastatic LNs that will receive immunotherapy. Surgical removal of LNs to prevent metastatic recurrence, including sentinel lymph node biopsy (SLNB) and completion lymph node dissection (CLND), are performed in routine practice. However, removing LNs eliminates opportunities for generating anti-cancer immune responses that are enhanced with immune checkpoint blockade (ICB). Balancing the potential risks and benefits of LN surgery is necessary to maximize outcomes for patients. In contrast to mouse studies using ectopic tumor implantation, the phase III clinical trialNCT00636168found patients with completely resected stage III melanoma (primary tumor, sentinel LNs and disease-related LNs all removed) still benefited from anti-CTLA4 inhibition. Our retrospective analysis demonstrated that stage III melanoma patients with SLNB or CLND have similar response to anti-PD1 inhibition. Using orthotopic murine mammary carcinoma and melanoma that have spontaneous LN metastases, we show that responses to ICB persist in mice after resection of TDLNs. Mechanistically, after disruption of normal lymphatic drainage, antigen can access adjacent lymphatic basins (lymphosomes) and be transported to distant LNs, which extends the responsiveness to ICB. By evaluating head and neck cancer patients treated by neoadjuvant durvalumab and irradiation, we show that distant LNs remain reactive in the absence of metastatic disease in ICB responder patients after tumor and disease related-LN resection, indicating anti-cancer immune reactions occur in distant LNs after TDLN removal in patients. Additionally, after TDLN dissection in mouse models, ICB delivered to distant LNs generated greater survival benefit, compared to systemic administration. In complete responders, anti-tumor immune memory induced by ICB was systemic rather than confined within lymphoid organs. Based on these findings, we constructed a computational model to predict free antigen trafficking in patients that will undergo LN dissection. Collectively, we propose that ICB efficacy persists in tumors of the trunk and extremities after removing original TDLNs because antigen can be transported through interstitial tissues to adjacent lymphosomes to gain access to alternative LNs, where anti-cancer immune responses can be generated and maintained.

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Section: Discussionmentioning

confidence: 99%

Cancer immunotherapy response persists after lymph node resection

Zhou,

Menzel,

Baish

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Cell lysate not used for immunoprecipitation was utilized as the input control for target proteins. 77 …”

Section: Methodsmentioning

confidence: 99%

“…The proximity ligation assay (Millipore Sigma Duolink in situ PLA Probe # DUO92002) was performed as per the manufacturer’s instructions. 77 …”

Section: Methodsmentioning

confidence: 99%

“…After 2.5 weeks of treatment or if body weight and conditions indicated earlier endpoint, mice were sacrificed, and blood and tumors were collected for downstream applications. 77 …”

Section: Methodsmentioning

confidence: 99%

“…For correlation analysis, Pearson correlation coefficients were calculated using GraphPad Prism Software, 8.0.1. 26 , 77 …”

Section: Methodsmentioning

confidence: 99%

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Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors

Sheridan,

Chowdhury,

Wellslager

et al. 2024

iScience

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“Find Me” and “Eat Me” signals: tools to drive phagocytic processes for modulating antitumor immunity

Xiao,

Zhang,

Guo

et al. 2024

Cancer Communications

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Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect “find me” signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send “eat me” signals that are recognized by phagocytes via specific receptors. “Find me” and “eat me” signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro‐phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic “find me” and “eat me” signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between “find me” and “eat me” signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate “find me” and “eat me” signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine “find me” and “eat me” signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.

show abstract

Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis

Cited by 9 publications

References 66 publications

Cancer immunotherapy response persists after lymph node resection

Cancer immunotherapy response persists after lymph node resection

Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors

“Find Me” and “Eat Me” signals: tools to drive phagocytic processes for modulating antitumor immunity

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