VScancer cells do not exist in isolation, but live within a complex ecosystem that also includes immune cells, stromal cells, extracellular matrix, blood vessels and many other factors. Components of the tumor microenvironment constantly interact and influence each other, which can affect tumor behavior positively or negatively.
“Tumor cells can take advantage of their surrounding microenvironment – co-opting nutrients and blocking host immune surveillance and response. Importantly, the tumor microenvironment can also curb tumor growth and prevent metastasis,” Janis says. Taube, professor of dermatology and pathology and co-director of the Mark Foundation for Advanced Genomics and Imaging at Johns Hopkins University in Baltimore.”It’s a double-edged sword – and so it’s about finding the right balance and to try to tip it more in favor of the host than the tumor.”
Given the diversity of cell types and molecules that make up the tumor microenvironment, it is necessary to apply a systems biology approach to study it.
“Because of the inherent complexity of the tumor microenvironment, changing one thing is going to have ripple effects,” says Dario A. Vignali, interim chair and professor emeritus of the Department of Immunology at the University of Pittsburgh and Hillman Cancer. UPMC Center. “You can compare it to a trampoline – if one person stands on one end, there are consequences for anyone else who stands on it.”
Dissecting the complexity of the tumor microenvironment can reveal clues as to why some cancers respond well to certain treatments while others don’t respond at all or develop resistance over time – and identify potential new vulnerabilities to exploit.
Targeting the tumor microenvironment
In recent years, a new class of immunotherapies targeting immune cells in the tumor microenvironment has transformed the treatment of certain types of cancer. Leading this revolution are so-called immune checkpoint inhibitors that reinvigorate specialized immune cells – called T cells – to recognize, attack and destroy cancer cells.
“These therapies can release the brake that tumors put on the immune system, allowing T cells to respond and help clear the tumor,” Taube says.
Although some tumors respond well to immune checkpoint blockade, unfortunately, the vast majority do not respond. Although the reasons for the high degree of variability between patients are complex, interactions between cancer cells and immune cells within the tumor microenvironment are likely to play an important role.
“There is a varying degree of immune infiltration in tumors, which has given rise to the analogy of an ‘immune desert’ or an ‘immune jungle’,” describes Vignali. “There is good data suggesting that tumors that are heavily infiltrated by the immune system are more susceptible to the effects of these immunotherapies.”
Researchers are working to define the characteristics of the tumor microenvironment that influence how a person’s cancer responds to immune checkpoint inhibitors – to identify new biomarkers to personalize treatment and find ways to increase the effectiveness of these drugs.
“We need to understand the effect of these treatments on the whole tumor microenvironment, rather than just focusing on the specific type of cell they target,” says Vignali. “A killer T cell is not isolated – it interacts with many other cells, which will have ripple effects on how the tumor responds to checkpoint inhibition.”
Single cell technologies
Until recently, researchers were limited to profiling whole tumor samples using “mass sequencing” approaches. But the advent of new single-cell technologies allows them to profile immune cell populations in the tumor microenvironment in greater detail.
“We can get an enormous amount of information from a single cell – it’s been a game-changer,” Vignali enthuses.
Single-cell transcriptomics allows the analysis of the abundance and sequences of RNA molecules, while epigenomics is the genome-wide mapping of DNA methylation, histone protein modification, chromatin accessibility and chromosome conformation. Another recent innovation is the cellular indexing of transcriptomes and epitopes by sequencing (ISCED-seq), which allows researchers to simultaneously capture RNA expression and cell surface expression of specific proteins on the same cell. Sequencing immune cell receptors – such as the T cell receptor (TCR) and B cell receptor (BCR) – can provide another dimension of information to characterize their specificity, function and phenotype.
“For example, we think of killer T cells as one group — but really, when you look at them at the single-cell level, you’ll find that there are several distinct subsets within that population,” says Vignali. .
The application of single-cell multi-omics technologies allows researchers to ask questions about the tumor microenvironment that were previously out of reach.
“We’ve always been limited by how much tissue you can get from a patient, but now it’s possible to get a lot of information from even a small tumor biopsy,” says Vignali. “For example, we have an ongoing clinical trial where we are collecting tumor biopsies from patients before and after treatment. It’s not too invasive a procedure and it means we can look at the basic situation and then what has changed after the immunotherapy.
Map the tumor microenvironment
However, while single-cell technologies can shed light on the molecular characteristics of the cells that make up a tumor, they provide no insight into how the cells are spatially organized within their microenvironment.
Multiplex immunofluorescence (mIF) techniques are becoming an increasingly important tool for analyzing multiple cell types and their geographic relationships within the tumor microenvironment. The approach allows for simultaneous antibody-based detection of multiple markers on a single tissue section, but analysis and visualization of mIF data can be complex and time consuming. But lessons can be learned from the techniques already used by astronomers to map the universe.
“Our great achievement is that there are many similarities between celestial sphere description and tumor microenvironment annotation,” says Alexandre Szalay, Bloomberg Distinguished Professor of Physics and Astronomy at Johns Hopkins University. “The bottom line is that it’s all about characterizing spatial relationships – so what are nearby objects interacting with each other, and how can we represent that visually?”
A unique collaboration forged between Taube and Szalay led to the development of the AstroPath platformwhich enables comprehensive analysis of multispectral imaging datasets in tumor tissue sections at single-cell resolution.
“We use immunofluorescent tags on antibodies to label multiple markers on a section – and then we can identify each cell,” Taube says. “Using this approach, we can reconstruct multispectral images from an entire slide, giving us about a hundred times more tumor microenvironment data than was previously available.”
The duo are using this formidable technology to advance understanding of the interaction between cancer cells and the immune system and to identify predictive biomarkers of tumor response to immunotherapies. The development of the platform as an open resource for visualizing and analyzing spatially-resolved mIF datasets is already underway.
“THE Sloan Digital Sky Survey, which Alex helped design and curate, has had over three billion visits to its website to date,” says Taube. “We hope to make the tumor microenvironment equivalent to this resource, allowing people around the world to view and query this data.”
Understanding how the dynamic interactions of cancer cells with their surrounding microenvironment can influence behavior, prognosis, and tumor response to treatment could ultimately help transform patient care. Thanks to enormous advances in technology, researchers now have the tools to study the tumor microenvironment in greater detail than ever before.
“These interrogative technologies have opened the door to obtaining much more information at an exponential rate over the next decade,” says Vignali. “The capabilities are huge – and it’s almost a cliché, but the sky really is the limit!”
However, this presents new challenges with integrating and interpreting the multiple huge datasets generated – leading some researchers to search for solutions from unexpected sources.
“I’ve spent decades in astronomy working on these special tools – and I never thought it would have practical application,” Szalay says. “And now it’s clear that one day this work could actually save lives – and that’s incredibly rewarding.”
This history was originally published by Technology networksa trusted science news publication that provides high-quality coverage of analytical chemistry, life sciences, drug discovery and neuroscience.