Interrogation of endothelial and mural cells in brain metastasis reveals key immune-regulatory mechanisms.

Brain metastasis (BrM) is a common malignancy, predominantly originating from lung, melanoma, and breast cancers. The vasculature is a key component of the BrM tumor microenvironment with critical roles in regulating metastatic seeding and progression. However, the heterogeneity of the major BrM vascular components, namely endothelial and mural cells, is still poorly understood. We perform single-cell and bulk RNA-sequencing of sorted vascular cell types and detect multiple subtypes enriched specifically in BrM compared to non-tumor brain, including previously unrecognized immune regulatory subtypes. We integrate the human data with mouse models, creating a platform to interrogate vascular targets for the treatment of BrM. We find that the CD276 immune checkpoint molecule is significantly upregulated in the BrM vasculature, and anti-CD276 blocking antibodies prolonged survival in preclinical trials. This study provides important insights into the complex interactions between the vasculature, immune cells, and cancer cells, with translational relevance for designing therapeutic interventions.

The local microenvironment drives activation of neutrophils in human brain tumors.

Neutrophils are abundant immune cells in the circulation and frequently infiltrate tumors in substantial numbers. However, their precise functions in different cancer types remain incompletely understood, including in the brain microenvironment. We therefore investigated neutrophils in tumor tissue of glioma and brain metastasis patients, with matched peripheral blood, and herein describe the first in-depth analysis of neutrophil phenotypes and functions in these tissues. Orthogonal profiling strategies in humans and mice revealed that brain tumor-associated neutrophils (TANs) differ significantly from blood neutrophils and have a prolonged lifespan and immune-suppressive and pro-angiogenic capacity. TANs exhibit a distinct inflammatory signature, driven by a combination of soluble inflammatory mediators including tumor necrosis factor alpha (TNF-ɑ) and Ceruloplasmin, which is more pronounced in TANs from brain metastasis versus glioma. Myeloid cells, including tumor-associated macrophages, emerge at the core of this network of pro-inflammatory mediators, supporting the concept of a critical myeloid niche regulating overall immune suppression in human brain tumors.

Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation.

The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed immune activation may ensue. To interrogate potential roles of T cells in this process, we profiled these cells from individuals with primary or metastatic brain cancers via integrated analyses on the single-cell and bulk population levels. Our analysis revealed similarities and differences in T cell biology between individuals, with the most pronounced differences observed in a subgroup of individuals with brain metastasis, characterized by accumulation of CXCL13-expressing CD39+ potentially tumor-reactive T (pTRT) cells. In this subgroup, high pTRT cell abundance was comparable to that in primary lung cancer, whereas all other brain tumors had low levels, similar to primary breast cancer. These findings indicate that T cell-mediated tumor reactivity can occur in certain brain metastases and may inform stratification for treatment with immunotherapy.

[Oncology: what's new in 2022]. / Oncologie : ce qui a changé en 2022.

The past year has brought several innovations in medical oncology, opening up promising new options for many solid tumors, both localized and metastatic. Immunotherapy, a real spearhead of emerging therapies in metastatic diseases, is seeing its use extend to adjuvant and neoadjuvant modalities, particularly in colon and lung cancers. 2022 also sees a great deal of focus on targeted therapies, as well as on antibody-drug conjugates, which creates new standards in both breast and lung cancers. Here we present the major advances in solid tumors.

L'année écoulée a apporté son lot d'innovations en oncologie médicale, ouvrant de nouvelles options prometteuses pour bon nombre de tumeurs solides, qu'elles soient localisées ou métastatiques. L'immunothérapie, véritable fer de lance des thérapies émergentes dans les maladies métastatiques, voit son usage s'étendre à des modalités adjuvantes et néoadjuvantes, notamment dans les cancers du côlon et du poumon. 2022 donne également la part belle aux thérapies ciblées mais aussi aux conjuguées anticorps-médicaments qui apportent de nouveaux standards tant pour les cancers du sein que du poumon. Nous vous présentons ici les avancées majeures concernant les tumeurs solides.

Attenuation of the pro-inflammatory signature of lung cancer-derived mesenchymal stromal cells by statins.

Solid tumor growth triggers a dynamic host response, which recapitulates wound healing and defines the tumor microenvironment (TME). In addition to the action of the tumor cells themselves, the TME is maintained by a myriad of immune and stromal cell-derived soluble mediators and extracellular matrix components whose combined action supports tumor progression. However, therapeutic targeting of the TME has proven challenging because of incomplete understanding of the tumor-host crosstalk at the molecular level. Here, we investigated the crosstalk between mesenchymal stromal cells (MSCs) and primary cancer cells (PCCs) from human squamous cell lung carcinoma (SCC). We discovered that PCCs secrete CCL3 and stimulate IL-6, CCL2, ICAM-1 and VCAM-1 expression in MSCs and that the MSC-PCC crosstalk can be disrupted by the lipid-lowering drug simvastatin, which displays pleiotropic effects on cell metabolism and suppresses IL-6 and CCL2 production by MSCs and CCL3 secretion by PCCs. In addition, simvastatin inhibited spheroid formation by PCCs and negatively affected PCC survival. Our observations demonstrate that commonly used statins may be repurposed to target the TME in lung carcinoma.

Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression.

Mesenchymal stem or stromal cells (MSCs) are pluripotent cells implicated in a broad range of physiological events, including organogenesis and maintenance of tissue homeostasis as well as tissue regeneration and repair. Because their current definition is somewhat loose - based primarily on their ability to differentiate into a variety of mesenchymal tissues, adhere to plastic, and express, or lack, a handful of cell surface markers - MSCs likely encompass several subpopulations, which may have diverse properties. Their diversity may explain, at least in part, the pleiotropic functions that they display in different physiological and pathological settings. In the context of tissue injury, MSCs can respectively promote and attenuate inflammation during the early and late phases of tissue repair. They may thereby act as sensors of the inflammatory response and secrete mediators that boost or temper the response as required by the stage of the reparatory and regenerative process. MSCs are also implicated in regulating tumor development, in which they are increasingly recognized to play a complex role. Thus, MSCs can both promote and constrain tumor progression by directly affecting tumor cells via secreted mediators and cell-cell interactions and by modulating the innate and adaptive immune response. This review summarizes our current understanding of MSC involvement in tumor development and highlights the mechanistic underpinnings of their implication in tumor growth and progression. © 2020 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis.

Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs) on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis.

Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets.

Mesenchymal stem cells (MSCs) display pleiotropic functions, which include secretion of soluble factors with immunosuppressive activity implicated in cancer progression. We compared the immunomodulatory effects on natural killer (NK) cells of paired intratumor (T)- and adjacent non-tumor tissue (N)-derived MSCs from patients with squamous cell lung carcinoma (SCC). We observed that T-MSCs were more strongly immunosuppressive than N-MSCs and affected both NK function and phenotype, as defined by CD56 expression. T-MSCs shifted NK cells toward the CD56dim phenotype and differentially modulated CD56bright/dim subset functions. Whereas MSCs affected both degranulation and activating receptor expression in the CD56dim subset, they primarily inhibited interferon-γ production in the CD56bright subset. Pharmacological inhibition of prostaglandin E2 (PGE2) synthesis and, in some MSCs, interleukin-6 (IL-6) activity restored NK function, whereas NK cell stimulation by PGE2 alone mimicked T-MSC-mediated immunosuppression. Our observations provide insight into how stromal responses to cancer dampen NK cell activity in human lung SCC.