A Bird’s Eye View of the Tumor Microenvironment

The tumor microenvironment is a battleground where infiltrating immune cells either subdue or promote a cancer, all while cancer cells try to dampen the body’s defenses.^1,2 Scientists have studied how tumor and immune cells interact, but few researchers have explored the spatial organization of immune cells in the tumor microenvironment in fine detail.³ Now, by using advanced imaging techniques, cancer biologists have characterized the architectural arrangement of immune cells in human lung tumors.⁴ Their findings, published in Cancer Discovery, could help researchers understand why some tumors respond to immunotherapies better than others.

“One of the important things we as a field need to do is start really understanding what’s going on immunologically in the tumor in order to make treatment decisions,” said Kristin Anderson, a cancer immunologist at the University of Virginia who was not involved with the work. “We should be using really in-depth profiling like the authors did in this article,” she added.

Just as someone can peer down at whole towns from an airplane window, the team sought out an aerial view of the tumor microenvironment, intent on capturing immune cell neighborhoods. “We’re using recent imaging technologies that allow us to not only understand the cell type but where they are in the microenvironment,” said Mihaela Angelova, a cancer immunologist at the Francis Crick Institute and study coauthor. Using imaging mass cytometry on early-stage lung tumors, Angelova and her team simultaneously detected dozens of immune cell types in the tissues. By collecting a census of the immune cells at every post code in and around the tumor, they produced an atlas of the immune microenvironment.

The team discovered that the immune cell makeup of each tumor fell into one of four archetypes, akin to different kinds of human settlements. One of the archetypes resembled a busy metropolis: T cells, B cells, and macrophages populated the tumor like city dwellers. “We would hypothesize in the field that if a patient’s tumor has lots of T cells in it already, [then] those patients are more likely to respond to a checkpoint inhibitor,” Anderson commented.

Other tumor tissues housed sparser immune cell populations. In one archetype, Angelova and her team found that immune cells sprawled the suburbs around the cancer but did not make themselves at home inside the tumor itself. Another kind of microenvironment resembled the backcountry. Just as steep slopes across badlands create physical barriers that deter human civilization, these tumor microenvironments contained an abundance of fibroblasts blocking entry to immune cells. For these two archetypes, immune cells were generally absent from inside the tumors, so the cancers might not respond to immunotherapies. However, Emma Colliver, a computational biologist at University College London and study coauthor, noted that researchers could potentially target and breach the fibroblast barriers to facilitate immune cell access to the tumor.

Other tumors exhibited an influx of neutrophils more than any other immune cell. Upon following up on the patients who donated these tissues, the researchers discovered that tumors with this archetype showed an increased likelihood of metastasis. “Experimental studies have alluded to a role of neutrophils that could be important for metastasis, and now it’s good to see that paired with human data as well,” Angelova said. In the future, the researchers will explore how this cell type might facilitate cancer spread.

The team is currently studying the immune cell makeup of tumors from late-stage cancers collected during autopsies. “A portion of those patients may have received immunotherapies,” said Colliver. “That, of course, is showing us a context where ultimately these immunotherapies have not helped the patients,” she explained. 

Angelova said, “By categorizing these tumors, we can start to tailor and think about improving or personalizing those therapies.”

References

1. Peña-Romero AC, Orenes-Piñero E. Dual effect of immune cells within tumour microenvironment: Pro- and anti-tumour effects and their triggers. Cancers. 2022;14(7):1681. 
2. Yang L, et al. Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment. J Hematol Oncol. 2019;12(1):125. 
3. Li R, et al. Characterization of the tumor immune microenvironment in lung squamous cell carcinoma using imaging mass cytometry. Front Oncol. 2021;11:620989. 
4. Enfield KSS, et al. Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer. Cancer Discov. 2024;OF1-OF30.