Parikh, M. | Search bioRxiv

bioRxiv2023

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. Immunogenic tumors harbor spatially-localized multicellular immunity hubs defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. 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.

immunology↗

bioRxiv2022

Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade

Most patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Therefore, there is a critical need to identify early non-invasive biomarkers of response. We performed plasma proteomic analysis (>700 proteins) at three timepoints on 174 metastatic melanoma patients treated with ICB. We leverage independent training and testing cohorts to build a predictor of immunotherapy response that outperforms several tissue-based approaches. We found 217 differentially expressed proteins between ICB responders (R) and non-responders (NR), including a co-regulated module of proteins enriched in certain NR patients. By analyzing single-cell RNA-sequencing data of tumor biopsies from 32 patients, we dissected the relative contribution of cells in the tumor to proteins in circulation. The majority of proteins in the co-regulated NR module derived from tumor and myeloid cells. Amongst myeloid cells, we identified a subset of tumor-associated macrophages (TAMs) with a suppressive phenotype that expressed high levels of the co-regulated NR module, thus suggesting they are key drivers of non-response signatures. Together, our data demonstrates the utility of plasma proteomics in biomarker discovery and in understanding the biology of host response to tumors.

cancer biology↗