T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion

Hindley, James P.; Jones, Emma; Smart, Kathryn; Bridgeman, Hayley; Lauder, Sarah N.; Ondondo, Beatrice; Cutting, Scott; Ladell, Kristin; Wynn, Katherine K.; Withers, David R.; Price, David A.; Ager, Ann; Godkin, Andrew; Gallimore, Awen

doi:10.1158/0008-5472.can-12-1912

Cited by 94 publications

(142 citation statements)

References 32 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…Here, high densities of HEVs are associated with a reduced frequency of FoxP3 + regulatory T (Treg) cells. Similar data have also been obtained in an experimental model of carcinogen‐induced fibrosarcoma, where Treg cell depletion caused reduced tumour growth and increased HEV formation 65. Indeed, HEVs in solid tumours are regarded as positive prognostic indicators and patients are often disease free for longer, show reduced evidence of tumour metastasis and display improved survival rates 9, 65, 66, 67, 70.…”

Section: High Endothelial Venules At Elfssupporting

confidence: 73%

“…As such, targeting cytokines such as LT αβ to tumours may have therapeutic potential as demonstrated in experimental melanoma 72, 99. Recent studies also suggest that inhibition of Treg cell activities could promote endogenous anti‐tumour immune responses at ELFs 65, 100. In support of such approaches, a suppressive role for Treg cells in iBALT development has also recently been reported 136…”

Section: Concluding Remarks and Future Perspectives On The Therapeutimentioning

confidence: 91%

“…Immunotherapies that support the activities of ELFs therefore represent promising anti‐cancer treatments. These may include delivery of regulatory homeostatic chemokines and cytokines or interventions that block Treg involvement at ELFs 65, 100…”

Section: Elfs As Regulators Of Anti‐tumour Immunitymentioning

confidence: 99%

See 2 more Smart Citations

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

View full text Add to dashboard Cite

SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.

show abstract

Section: High Endothelial Venules At Elfssupporting

confidence: 73%

Section: Concluding Remarks and Future Perspectives On The Therapeutimentioning

confidence: 91%

See 1 more Smart Citation

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

View full text Add to dashboard Cite

show abstract

“…In these experiments, shutdown of afferent lymphatics was shown to significantly reduce HEV in lymph nodes with concomitant reduction in the degree of lymphocytic infiltrate. Although no HEV could be detected in the MCA‐induced tumors described here, it has been previously shown by our group that HEV can develop in these tumors when Tregs are depleted 14. It is thus possible that delivery of lymph, which may provide a source of key factors such as chemokines and cytokines, is essential for this process 32.…”

Section: Discussionmentioning

confidence: 58%

Progression of carcinogen‐induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics

Ondondo

Jones

Hindley

et al. 2013

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

The tumor microenvironment comprises newly formed blood and lymphatic vessels which shape the influx, retention and departure of lymphocytes within the tumor mass. Thus, by influencing the intratumoral composition of lymphocytes, these vessels affect the manner in which the adaptive immune system responds to the tumor, either promoting or impairing effective antitumor immunity. In our study, we utilized a mouse model of carcinogen‐induced fibrosarcoma to examine the composition of tumor‐infiltrating lymphocytes during tumor progression. In particular, we sought to determine whether CD4+Foxp3+ regulatory T cells (Tregs) became enriched during tumor progression thereby contributing to tumor‐driven immunosuppression. This was not the case as the proportion of Tregs and effector CD4+ T cells actually declined within the tumor owing to the unexpected accumulation of naïve T cells. However, we found no evidence for antigen‐driven migration of these T cells or for their participation in an antitumor immune response. Our data support the notion that lymphocytes can enter tumors via aberrantly formed blood and lymphatic vessels. Such findings suggest that targeting both the tumor vasculature and lymphatics will alter the balance of lymphocyte subpopulations that enter the tumor mass. A consideration of this aspect of tumor immunology may be critical to the success of solid cancer immunotherapies.

show abstract

“…Interestingly, tumor HEVs have been detected in murine B16 melanoma tumors after targeting of lymphotoxin a (LTa) within the tumor (12,13), and more recently in methylcholanthreneinduced fibrosarcomas upon depletion of regulatory T cells (Tregs) in FoxP3-DTR transgenic mice (14). In both cases, the presence of HEVs in the tumors was associated with T cell infiltration and tumor regression (12)(13)(14).…”

mentioning

confidence: 99%

High Endothelial Venule Blood Vessels for Tumor-Infiltrating Lymphocytes Are Associated with Lymphotoxin β–Producing Dendritic Cells in Human Breast Cancer

Martinet

Filleron

Guellec

et al. 2013

The Journal of Immunology

123

131

View full text Add to dashboard Cite

Blood vessels and tumor angiogenesis are generally associated with tumor growth and poor clinical outcome of cancer patients. However, we recently discovered that some blood vessels present within the tumor microenvironment can be associated with favorable prognosis. These vessels, designated tumor high endothelial venules (HEVs), appear to facilitate tumor destruction by allowing high levels of lymphocyte infiltration into tumors. In this study, we investigated the mechanisms regulating HEV blood vessels in human breast cancer. We found that lymphotoxin β was overexpressed in tumors containing high densities of HEVs (HEVhigh) and correlated to DC-LAMP, a marker of mature DCs. DCs were the main producers of lymphotoxin β in freshly resected HEVhigh breast tumor samples, and the density of DC-LAMP+ DCs clusters was strongly correlated with the density of tumor HEVs, T and B cell infiltration, and favorable clinical outcome in a retrospective cohort of 146 primary invasive breast cancer patients. Densities of tumor HEVs and DC-LAMP+ DCs were strongly reduced during breast cancer progression from in situ carcinoma to invasive carcinoma, suggesting that loss of tumor HEVs is a critical step during breast cancer progression. Finally, an increase in the infiltration of regulatory T cells was observed in HEVhigh breast tumors, indicating that tumor HEVs can develop in the presence of regulatory T cells. Together, our results support a key role for DCs and DC-derived lymphotoxin in the formation of tumor HEVs. These findings are important because novel therapeutic strategies based on the modulation of tumor HEVs could have a major impact on clinical outcome of cancer patients.

show abstract

T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion

Cited by 94 publications

References 32 publications

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Progression of carcinogen‐induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics

High Endothelial Venule Blood Vessels for Tumor-Infiltrating Lymphocytes Are Associated with Lymphotoxin β–Producing Dendritic Cells in Human Breast Cancer

Contact Info

Product

Resources

About