Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response


The organization of immune cells in human tumors is not well understood. We previously showed that immunogenic tumors harbor spatially-localized multicellular ‘immunity hubs’ defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and associated T cells. 

We now examined immunity hubs in pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade in humans. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11+ macrophages that preferentially interact with CD8 T cells. 

Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7+LAMP3+ dendritic cells, as well as chemokines that organize these cells. 

These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.

Webinar Learning Objectives:

  • Learn how to use single-cell RNA-seq datasets to design custom gene panels for effective spatial transcriptomics
  • Learn to uncover networks of interacting immune cells in space
  • Learn how the immune response is spatially organized within tumors

Nir Hacohen, PhD

Director of the Center for Cancer Immunology, Massachusetts General Hospital

Dr. Hacohen is Director of the Center for Cancer Immunology at Massachusetts General Hospital, David P. Ryan Professor at Harvard Medical School, and Director of the Center for Cell Circuits at the Broad Institute of MIT and Harvard. His group uses systems-level approaches to discover molecular and cellular mechanisms of immunity and to design personalized immunotherapies.

Using genetic and biochemical approaches, his group identified factors (such as signaling, transcription, splicing and chromatin regulators, as well as non-coding elements and variants) that underlie pathogen sensing and host-pathogen interactions.

He has contributed to the Human Cell Atlas by discovering new cell types, including human dendritic cell subsets and their progenitors, T cell activation states, and disease-associated immune cell states (from patients with bacterial/viral sepsis, lupus nephritis and cancer).

These studies led to the discovery of spatially-organized immune cell hubs within tumors. His group is reverse-translating these findings from human diseases to mouse models, with the goal of identifying therapeutic targets conserved across species.

He and his collaborators developed some of first personalized vaccines to target tumor-specific neoantigens in patients with melanoma and glioblastoma, and continue to innovate methods to discover, predict and induce responses against personalized tumor antigens.