A Spatial Proteomic Atlas of Tertiary Lymphoid Structures in Non-Small Cell Lung Cancer Identifies a Novel Predictive Class of Lymphoid Aggregates

Risom, T.; Jesudason, R.; Liu, E.; Hill, A.; Beig, N.; Foo, C.; Liu, O.; Fuentes, E.; Tai, L.; Prasad, K.; Giltnane, J.; Johnston, R. J.; McGinnis, L. M.

doi:10.64898/2026.05.14.723890

bioRxiv · 10.64898/2026.05.14.723890

A Spatial Proteomic Atlas of Tertiary Lymphoid Structures in Non-Small Cell Lung Cancer Identifies a Novel Predictive Class of Lymphoid Aggregates

Risom, T.·Jesudason, R.·Liu, E.·Hill, A.·Beig, N.·Foo, C.·Liu, O.·Fuentes, E.·Tai, L.·Prasad, K.·Giltnane, J.·Johnston, R. J.·McGinnis, L. M.

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Abstract

Tertiary lymphoid structures (TLS) predict benefit from immune checkpoint inhibitors (CPIs), yet mature, germinal-center-rich TLS are infrequent in solid tumors by histological review. Here, using 38-plex MIBI spatial proteomics across 165 lymphoid structures from 14 NSCLC resections, we establish a continuum of TLS maturity using high dimensional compositional, spatial, and molecular features. We demonstrate that histologically-defined lymphoid aggregates (LA) comprise a heterogeneous class of structures, which span this continuum of maturity. We identify a subset of lymphoid aggregates that harbor follicular dendritic cell networks, T follicular helper cells, and activated B cell states characteristic of mature TLS, yet are not readily distinguished from other LA structures in our histological review. We developed a novel digital pathology classifier to identify mature LAs in CPI trials, and demonstrate in a retrospective analysis of Atezolizumab in advanced NSCLC that the inclusion of mature LAs greatly expands the biomarker-eligible population while maintaining strong predicted benefit. Together, these data redefine the biological spectrum of tumor-associated lymphoid aggregates and provide a framework for implementing maturity-informed TLS biomarker strategies.

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Risom, T., Jesudason, R., Liu, E., Hill, A., Beig, N., Foo, C., Liu, O., Fuentes, E., Tai, L., Prasad, K., Giltnane, J., Johnston, R. J., McGinnis, L. M.. 2026-05-18. A Spatial Proteomic Atlas of Tertiary Lymphoid Structures in Non-Small Cell Lung Cancer Identifies a Novel Predictive Class of Lymphoid Aggregates. https://doi.org/10.64898/2026.05.14.723890

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