A research study has profiled, in a sweeping comparative analysis, the distinct immune landscapes of tumors that arise in the brain, or gliomas, and those that metastasize to the organ from the lungs, breast and skin. Published in the journal Cell, the study captures in granular detail how the functions, locations and characteristics of various immune cells sculpt the tumor microenvironment (TME) to thwart immune attack, support cancer cell survival and drive tumor progression.
"Looking at these tumors side by side, we could very clearly see the differences not just between primary and metastatic brain cancers but also high-grade versus low-grade gliomas, and then among metastases originating from different primary sites," says the author. "Without juxtaposing those different disease entities, we wouldn't have been able to discover how profoundly different their immune landscapes are."
Cancers selectively harness a variety of immune cells and even manipulate their gene expression programs to get them to suppress anti-tumor immune responses, aid metastasis, establish a blood supply and provide other critical support. Targeting such turncoat immune cells, or "reeducating" them to attack their host tumors, is now a major focus of cancer immunology.
In their study, Joyce and her colleagues surveyed the numbers and preferential locations of 14 subtypes of immune cells in 100 brain tumor samples obtained from patients. They also profiled the full spectrum of proteins in the samples and the global gene expression patterns of individual immune cells. They then integrated these richly detailed, large-scale analyses to comprehensively map the immune landscape of each tumor type and capture differences in the functional states of their resident immune cells.
This comparative analysis revealed that five types of immune cells predominantly sculpt the brain TME. These include monocyte-derived macrophages that enter the brain from elsewhere in the body; microglia, the brain's resident version of those cells; related myeloid cells called neutrophils; CD4+ T cells, which orchestrate and regulate immune responses; and the CD8+ (killer) T cells that destroy cancer cells and can be activated by checkpoint blockade immunotherapies. The specific composition of the immune landscapes and the functional states of their constituent cells are shaped by the interplay of the brain's unique biology and the innate characteristics of each type of tumor.
The study shows, for example, that brain metastases of melanoma--one of the few brain tumors that have responded to checkpoint blockade--have an abundance of T cells. Gliomas, which are rich in macrophages and microglia, hardly have any. "You can imagine," says the author, "that for gliomas, you would want to develop therapies that increase the infiltration of T cells into the microenvironment." For melanoma brain metastases, on the other hand, the primary aim would be to activate the existing T cells in the TME to attack cancer cells.
Differences abound even within gliomas. The researchers show that microglia predominate in low-grade gliomas that are characterized by a mutation in an enzyme known as IDH. High-grade gliomas or glioblastomas (GBMs) associated with a normal IDH gene have a greater abundance of macrophages that migrate into the brain from the blood circulation.
"Therapies to block macrophage infiltration into the brain might be more beneficial for the treatment of high-grade gliomas than the depletion of microglia," says the author. In addition, therapies that "reeducate" macrophages to attack rather than nurture cancer cells could prove effective against gliomas in general--a possibility the Joyce lab is exploring.
The findings also open exciting new areas for research. Brain metastases of breast cancer, for instance, were found to be teeming with neutrophils. The lab's previous studies found that these cells play an important role in establishing a niche in the lungs for breast cancer metastases. The team are now exploring how neutrophils might influence their growth in the brain as well.
"I think, and I hope, that these data will be a very important resource not only for my lab, but for the whole brain tumor community to help advance the development of immune-targeted therapies," says the senior author.
https://www.ludwigcancerresearch.org/news-releases/ludwig-lausanne-study-charts-the-immune-landscape-of-multiple-brain-cancers/
https://www.cell.com/cell/fulltext/S0092-8674(20)30569-9
Different immune landscape of multiple brain cancers
- 1,615 views
- Added
Edited
Latest News
New origin of deep brain waves
By newseditor
Posted 17 Apr
Starving cells hijack prote…
By newseditor
Posted 17 Apr
Miniature battery-free epid…
By newseditor
Posted 17 Apr
Molecular causes of differe…
By newseditor
Posted 16 Apr
Cell's 'garbage disposal' h…
By newseditor
Posted 16 Apr
Other Top Stories
Mapping ketamine's effects on brain
Read more
Cell-type-specific genetic risk contributes to distinct stages of A…
Read more
Hot hatha yoga potent antidepressant in a clinical trial
Read more
How bone marrow peripheral nerves promote hematopoietic and vascula…
Read more
Finding biomarker for inflammatory bowel disease using reverse meta…
Read more
Protocols
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Modular dual-color BiAD sen…
By newseditor
Posted 31 Mar
Publications
The immunobiology of herpes…
By newseditor
Posted 17 Apr
Circulating microbiome DNA…
By newseditor
Posted 17 Apr
Spindle oscillations in com…
By newseditor
Posted 17 Apr
Oligodendroglial macroautop…
By newseditor
Posted 17 Apr
COPII with ALG2 and ESCRTs…
By newseditor
Posted 17 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar