CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10

Guldner, Ian H.; Wang, Qingfei; Yang, Lin; Golomb, Samantha M.; Zhao, Zhuo; Lopez, Jacqueline; Brunory, Abigail; Howe, Erin N.; Zhang, Yizhe; Palakurthi, Bhavana; Barron, Martin; Gao, Hongyu; Xuei, Xiaoling; Liu, Yunlong; Li, Jun; Chen, Danny Z.; Landreth, Gary E.; Zhang, Siyuan

doi:10.1016/j.cell.2020.09.064

“…When they performed mechanistic in-vitro and in-vivo studies they found C-X-C motif chemokine ligand 10 (Cxcl10) promoted BrMs, and they further characterized to elucidate the mechanism behind this. Investigation of publicly available human CNS myeloid RNAseq datasets, they found increased expression of Vsir (VISTA) and CD274 (PD-L1) in the myeloid cells [20]. In addition, they found co-inhibition of PD-L1 and VISTA in a mouse model of brain metastasis reduced the metastatic burden.…”

Section: Discussionmentioning

confidence: 98%

“…With respect to Central Nervous System metastatic disease, recent work by Guldner and coworkers have identified brain resident myeloid cells to be inducing an immunosuppressive microenvironment, thus promoting metastasis [20]. This study generated mouse models of BrMs to derive functional understanding of the myeloid cell population in this disease.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of Immune Cell Subsets of Tumour Infiltrating Lymphocytes in Brain Metastases

Croft¹,

Chittoory²,

Nguyên³

et al. 2021

Preprint

2

0

View full text Add to dashboard Cite

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

show abstract

“…When they performed mechanistic in-vitro and in-vivo studies they found C-X-C motif chemokine ligand 10 (Cxcl10) promoted BrMs, and as this chemokine is an immune modulator, they further characterized to elucidate the mechanism behind it. Investigation of publicly available human CNS myeloid RNAseq datasets, they found increased expression of Vsir (VISTA) and CD274 (PD-L1) in the myeloid cells [20]. In addition, they found co-inhibition of PD-L1 and VISTA in a mouse model of brain metastasis reduced the metastatic burden.…”

Section: Discussionmentioning

confidence: 99%

“…Since this discovery, knowledge on the role and function of VISTA in many cancers have been uncovered [15][16][17][18][19]. Furthermore, recent reports on mouse models of brain metastasis suggest VISTA blockade along with anti-PD L1 reduces BrM outgrowth and additionally, the release of cytokine Cxcl10 from tumor cells results in recruitment of VISTA expressing myeloid cells leading to T-cell suppression [20].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterisation of immune cell subsets of tumour infiltrating lymphocytes in brain metastases

Croft

¹

,

Chittoory

²

,

Nguyen

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

show abstract

Understanding the heterogeneous immune repertoire of brain metastases for designing next‐gen therapeutics

Wang,

Chen

2023

Brain-X

0

View full text Add to dashboard Cite

Approximately 20% of cancer patients experience brain metastases in the advanced stages as circulating tumor cells migrate to and colonize the brain microvasculature. Due to the challenges associated with biopsies, our understanding of the tumor microenvironment and heterogeneity in brain metastases remains limited, hindering the development of systemic approaches for detection and treatment. Emerging evidence suggests that specific brain metastases induce a substantial level of immune activation and infiltration, which provides an opportunity to design specific immunotherapies targeting brain metastases. This perspective aims to summarize recent advancements in molecular profiling of the immune repertoires of brain metastases using biopsy‐based approaches, with an emphasis on tumor‐reactive T cells. Additionally, we discuss the potential of alternative tissues and technologies that offer improved temporal resolution, throughput, and fidelity for tracking tumor dynamics.

show abstract

CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10

Cited by 96 publications

References 54 publications

Characterisation of Immune Cell Subsets of Tumour Infiltrating Lymphocytes in Brain Metastases

Characterisation of Immune Cell Subsets of Tumour Infiltrating Lymphocytes in Brain Metastases

Characterisation of immune cell subsets of tumour infiltrating lymphocytes in brain metastases

Understanding the heterogeneous immune repertoire of brain metastases for designing next‐gen therapeutics

Contact Info

Product

Resources

About