scholarly journals Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alba Nicolas-Boluda ◽  
Javier Vaquero ◽  
Lene Vimeux ◽  
Thomas Guilbert ◽  
Sarah Barrin ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Lysyl Oxidase ◽  
Treatment Strategies ◽  
Mouse Tumor ◽  
Tumor Microenvironments ◽  
T Cell Migration ◽  
Ecm Architecture

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

scholarly journals Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

2020 ◽  
Author(s):  
Alba Nicolas-Boluda ◽  
Javier Vaquero ◽  
Sarah Barrin ◽  
Chahrazade Kantari-Mimoun ◽  
Matteo Ponzo ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Lysyl Oxidase ◽  
Treatment Strategies ◽  
Mouse Tumor ◽  
Tumor Microenvironments ◽  
T Cell Migration ◽  
Ecm Architecture

ABSTRACTOnly a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

scholarly journals Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a function in T-cell migration

Immunology ◽  
2003 ◽  
Vol 108 (1) ◽  
pp. 32-41 ◽  
Author(s):  
Isabel Correa ◽  
Tim Plunkett ◽  
Anda Vlad ◽  
Arron Mungul ◽  
Jessica Candelora-Kettel ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Muc1 Expression ◽  
T Cell Migration

Targeting tumor-associated macrophage (TAM) mediated inhibition of T-cell migration in prostate cancer using epigenetic modifying agents.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 166-166
Author(s):  
David Kosoff ◽  
Leigh Ellis ◽  
David J. Beebe ◽  
Joshua Michael Lang
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Cancer Cell Line ◽  
Cytotoxic T Cell ◽  
Culture Systems ◽  
T Cell Migration

166 Background: Cytotoxic T lymphocytes (CTLs) perform vital anti-tumor functions and are critical to the efficacy of many anticancer therapies. In prostate cancer, the characteristic paucity of activated CTLs within the tumor microenvironment (TME) may be a key factor in disease progression and likely underlies the limited role for immune checkpoint inhibitors (ICIs) in prostate cancer treatment. In this study, we utilized novel microfluidic technologies to evaluate whether TAMs may be driving the exclusion of T cells from the prostate TME and whether the immunosuppressive functions of TAMs could be modified by epigenetic modifying agents. Methods: Primary macrophages and autologous T cells were derived from peripheral blood samples of prostate cancer patients at the University of Wisconsin. Mono-, co-, and tri-culture systems of macrophages, T cells, and 22RV1 cells (androgen-dependent prostate cancer cell line) were cultured in 2D and 3D in microfluidic cell culture platforms. Culture systems were treated with the EZH2 inhibitors (EZH2i) DZNep or EPZ-6438 or left untreated. Macrophages were also treated with M1 (IFN-g) and M2 (IL-4) polarizing cytokines. Systems were analyzed for T cell migration as well as mRNA and protein expression in each cell population. Results: Autologous macrophages inhibited activated T cell migration towards tumor cells in a multi-cellular microscale TME. T cell migration was restored through treatment with EZH2i. Gene expression analysis identified that EZH2i altered macrophage gene expression in the unpolarized and M1/M2 polarized states. In particular, there was increased expression of genes involved in T cell recruitment/chemotaxis, including CXCL10, CXCL11, CXCL12, following EZH2i treatment. Conclusions: We used novel microfluidic technologies to model and analyze multicellular TMEs using primary, patient-derived cells. We demonstrate that TAM-mediated suppression of T cell migration is mediated, in part, through epigenetic pathways, which can be targeted with EZH2i. Treatment with EZH2i, alone or in combination other therapies such as ICIs, may enhance cytotoxic T cell migration and activity in primary prostate cancer.

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