Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Reticker-Flynn, Nathan E.; Zhang, Weiruo; Belk, Julia A.; Basto, Pamela A.; Escalante, Nichole K.; Pilarowski, Genay; Bejnood, Alborz; Martins, Maristela Santini; Kenkel, Justin A.; Linde, Ian L.; Bagchi, Sreya; Yuan, Robert; Chang, Serena; Spitzer, Matthew H.; Carmi, Yaron; Cheng, Jinghui; Tolentino, Lorna; Choi, Okmi; Wu, Nancy; Kong, Christina S.; Gentles, Andrew J.; Sunwoo, John B.; Satpathy, Ansuman T.; Plevritis, Sylvia K.; Engleman, Edgar G.

doi:10.1016/j.cell.2022.04.019

Cited by 158 publications

(132 citation statements)

References 119 publications

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“…In our data, we observed that elevated LRRC59 expression was significantly associated with a positive nodal status, but the underlying mechanisms underpinning lymph node (LN) metastasis remain unexplored. Recent studies have shown that stress-related RNA helicase protein Ddx21 [28] , metabolic pathway regulatory factors YAP/TAZ [29] , and specific immune environment in LN might facilitate tumor colonization and metastasis [30] . We found that LRRC59 is significantly correlated with multiple stress-related genes in TCGA-BLCA data including DDX21 (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

Pei

Zhu

Zhuang

et al. 2022

Translational Oncology

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Section: Discussionmentioning

confidence: 99%

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

Pei

Zhu

Zhuang

et al. 2022

Translational Oncology

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“…However, this is not consistent with the pathophysiology of metastatic spread in melanoma. Reticker-Flynn et al have recently demonstrated a “Metastatic Tolerance” model, where lymph node colonization by tumor cells induces an immune tolerance, facilitating distant metastasis [ 30 ]. When lympho-systemic spread and tumor-immune tolerance have already occurred, it is not plausible that ILR creates a new channel for the spread of tumor cells that are located distally.…”

Section: Discussionmentioning

confidence: 99%

Higher Rate of Lymphedema with Inguinal versus Axillary Complete Lymph Node Dissection for Melanoma: A Potential Target for Immediate Lymphatic Reconstruction?

et al. 2022

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Background: The present study was conducted to define the lymphedema rate at our institution in patients undergoing axillary (ALND) or inguinal (ILND) lymph node dissection (LND) for melanoma. It aimed to examine risk factors predisposing patients to a higher rate of lymphedema, highlighting which patients could be targeted for immediate lymphatic reconstruction (ILR). Methods: A retrospective chart review was conducted between October 2015 and July 2020 to identify patients who had undergone ALND or ILND for melanoma. The main outcome measures were rates of transient and permanent lymphedema. Univariate and multivariate analyses were performed to assess the relationship between lymphedema rate and factors related to patient characteristics, surgical procedure, pathology findings, and adjuvant treatment. Results: Between October 2015 and July 2020, 66 patients underwent LND for melanoma: 34 patients underwent ALND and 32 patients underwent ILND. At a median follow-up of 29 months, 85.3% (n = 29) of patients having had an ALND did not experience lymphedema, versus 50.0% (n = 16) of ILND (p = 0.0019). The rates of permanent lymphedema for patients having undergone ALND and ILND were 11.8% (n = 4) and 37.5% (n = 12) respectively (p = 0.016, NS). The rate of transient lymphedema was 2.9% (n = 1) for ALND and 12.5% (n = 4) for ILND (p = 0.13, NS). On univariate analysis, the location of LND and wound infection were found to be significant factors for lymphedema. On multivariate analysis, only the location of LND remained a significant predictor, with the inguinal location predisposing to lymphedema. Conclusion: This study highlights the high rate of lymphedema following ILND for melanoma and is a potential target for future patients to be considered for ILR.

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“…Often, lymph node metastasis serves as the tumor-specific immune tolerance mechanism for subsequent distant metastasis. 191 Tumor-educated B-cells produce pathogenic IgGs to bind HSPA4 to precondition lymph node niche and promote lymph node metastasis 192 (Fig. 4 ).…”

Section: Preconditioning the Metastatic Niche Vs Preconditioning The ...mentioning

confidence: 99%

Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis

Jinesh

Brohl

2022

Sig Transduct Target Ther

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Metastasis is a pivotal event that accelerates the prognosis of cancer patients towards mortality. Therapies that aim to induce cell death in metastatic cells require a more detailed understanding of the metastasis for better mitigation. Towards this goal, we discuss the details of two distinct but overlapping pathways of metastasis: a classical reversible epithelial-to-mesenchymal transition (hybrid-EMT)-driven transport pathway and an alternative cell death process-driven blebbishield metastatic-witch (BMW) transport pathway involving reversible cell death process. The knowledge about the EMT and BMW pathways is important for the therapy of metastatic cancers as these pathways confer drug resistance coupled to immune evasion/suppression. We initially discuss the EMT pathway and compare it with the BMW pathway in the contexts of coordinated oncogenic, metabolic, immunologic, and cell biological events that drive metastasis. In particular, we discuss how the cell death environment involving apoptosis, ferroptosis, necroptosis, and NETosis in BMW or EMT pathways recruits immune cells, fuses with it, migrates, permeabilizes vasculature, and settles at distant sites to establish metastasis. Finally, we discuss the therapeutic targets that are common to both EMT and BMW pathways.

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Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Cited by 158 publications

References 119 publications

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

Higher Rate of Lymphedema with Inguinal versus Axillary Complete Lymph Node Dissection for Melanoma: A Potential Target for Immediate Lymphatic Reconstruction?

Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis

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