Spatial study of lung cancer reveals immune markers of response to immunotherapy

Researchers visualize how immune cells are spatially organized within tumors and show that certain immune “hubs” are linked to better treatment responses.

Microscopy image of human lung tumor tissue with an immunity hub circled
Credit: Chen JH et al. Nature Immunology. doi: 10.1038/s41590-024-01792-2 (2024)
Scientists used a microscope to visualize an immunity hub (yellow and green) in human lung tumor tissue (blue).

Most patients with cancer who are treated with immunotherapies called PD-1 inhibitors don’t respond to the treatments and many researchers have been trying to figure out why by studying immune cells in human tumors. Scientists at the Broad Institute of MIT and Harvard, Brigham and Womens’ Hospital, and Massachusetts General Hospital (MGH) focused on non-small cell lung cancer, the leading cause of cancer death. They analyzed individual immune cells from human lung tumor samples taken from 68 people before they were treated with PD-1 inhibitors. They mapped the cells’ genetic activity as well as the location of the cells in the tumors. 

The team found organized hubs of immune cells, or "immunity hubs", within some tumors. Tumors from people who responded well to PD-1 blockers tended to have a subtype of hub, called “stem-immunity hubs”, that consisted of specific types of immune cells and signaling molecules known to drive effective anti-tumor responses. The work was published in Nature Immunology

Two members of the research team, Nir Hacohen, co-senior author of the study, an institute member at Broad and director of the Center of Cancer Immunology at MGH, and Jonathan Chen, co-first author, a member of the Hacohen lab, and an investigator in the department of pathology at MGH describe their findings and how they are now translating them into potential diagnostics and therapeutics. 


Tell us more about these immunity hubs.

Networks of cells are critical in mediating immune responses. How do immune cells organize within tumors to effectively eliminate cancer cells?

In 2021, we reported the discovery of a network of immune cells in colorectal cancer. We called these networks “immunity hubs.” These consist of activated T cells abutting tumor and immune myeloid cells expressing T cell-attracting molecules. This finding suggested the existence of a positive feedback loop in which activated T cells drive further T cell recruitment by local cells in the tumor.

We reasoned that immunity hubs might be predictive of response to immunotherapy because they were enriched in a class of colorectal tumors known to have higher rate of response to PD-1 blockade immunotherapy. However, while our study of colorectal samples includes this class of tumors, the patients in our study were not treated with immunotherapy.

In this new study, we sought to answer whether immunity hubs are indeed predictive of response to standard of care immunotherapy. We studied non-small cell lung cancer (NSCLC), which is commonly treated with PD-1 blockade immunotherapy.


What did you find in your study?

We found that patients without immunity hubs in their tumors prior to PD-1 blockade therapy had poor outcomes relative to patients with hubs. Critically, we discovered the “stem-immunity” hub, a subtype of immunity hub that is strongly associated with favorable immunotherapy response.

Stem-immunity hubs were enriched for a type of T cell that is remarkable for its ability to divide and invigorate the antitumor immune response after PD-1 blockade. So the finding of these stem-immunity hubs represents a new way to think about how the immune response is organized in human cancer.


How important was the spatial analysis in your study?

This high-resolution spatial approach allowed us to discover important cell-cell interactions that may regulate the formation and function of these hubs.


What are the implications of your findings?

The most obvious implication of our work is that we can use the presence of the immunity hub, particularly the stem-immunity hub subclass, as a biomarker to predict response to immunotherapy.

The current standard biomarker for prediction of immunotherapy response is PD-L1 antibody staining, but it can be inaccurate and difficult to use. We are currently testing a simple two-marker tissue stain that reflects immunity and can be assessed by pathologists using a standard workflow.

We think the immunity hub may be how the immune system organizes to fight tumors.

Therefore, we aim to develop therapeutics based on findings in this study to augment immunity hubs and support the anti-tumor immune response.

Adapted from a Mass General Research Spotlight


This research was supported in part by Novartis as part of the MGH–Novartis Alliance, National Institutes of Health, National Cancer Institute, MGH Fund for Medical Discovery, MGH Krantz Stewardship, UROP funds from Massachusetts Institute of Technology, SU2C Phillip A. Sharp Award, Mark Foundation for Cancer Research, SITC/AstraZeneca Forward Fund, Happy Lungs Foundation, and the BWH-Broad Institute Collaborative Research Award.

Paper cited:

Chen JH, Nieman LT, Spurrell M et al. Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy. Nature Immunolology. Online March 19, 2024. DOI: 10.1038/s41590-024-01792-2