Spatial dynamics of tertiary lymphoid aggregates in head and neck cancer: insights into immunotherapy response

Sadeghirad, H; Monkman, J; Tan, CW; Liu, N; Yunis, J; Donovan, ML; Moradi, A; Jhaveri, N; Perry, C; Adams, MN; O&#39;Byrne, K; Warkiani, ME; Ladwa, R; Hughes, BGM; Kulasinghe, A

Author(s): Sadeghirad, H; Monkman, J; Tan, CW; Liu, N; Yunis, J; Donovan, ML; Moradi, A; Jhaveri, N; Perry, C; Adams, MN; O'Byrne, K; Warkiani, ME; Ladwa, R; Hughes, BGM; Kulasinghe, A;
Details: Publication Year 2024-07-24,Volume 22,Issue #1,Page 677
Journal Title: Journal of Translational Medicine
Abstract: BACKGROUND: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally has a poor prognosis for patients with limited treatment options. While incorporating immune checkpoint inhibitors (ICIs) has now become the standard of care, the efficacy is variable, with only a subset of patients responding. The complexity of the tumor microenvironment (TME) and the role of tertiary lymphoid structures (TLS) have emerged as critical determinants for immunotherapeutic response. METHODS: In this study, we analyzed two independently collected R/M HNSCC patient tissue cohorts to better understand the role of TLS in response to ICIs. Utilizing a multi-omics approach, we first performed targeted proteomic profiling using the Nanostring GeoMx Digital Spatial Profiler to quantify immune-related protein expression with spatial resolution. This was further characterized by spatially resolved whole transcriptome profiling of TLSs and germinal centers (GCs). Deeper single-cell resolved proteomic profiling of the TLSs was performed using the Akoya Biosciences Phenocycler Fusion platform. RESULTS: Our proteomic analysis revealed the presence of T lymphocyte markers, including CD3, CD45, and CD8, expressing cells and upregulation of immune checkpoint marker PD-L1 within tumor compartments of patients responsive to ICIs, indicative of 'hot tumor' phenotypes. We also observed the presence of antigen-presenting cells marked by expression of CD40, CD68, CD11c, and CD163 with upregulation of antigen-presentation marker HLA-DR, in patients responding to ICIs. Transcriptome analysis of TLS and GCs uncovered a marked elevation in the expression of genes related to immune modulation, diverse immune cell recruitment, and a potent interferon response within the TLS structure. Notably, the distribution of TLS-tumor distance was found to be significantly different across response groups (H = 9.28, p = 0.026). The proximity of TLSs to tumor cells was found to be a critical indicator of ICI response, implying that patients with TLSs located further from tumor cells have worse outcomes. CONCLUSION: The study underscores the multifaceted role of TLSs in modulating the immunogenic landscape of the TME in R/M HNSCC, likely influencing the efficacy of ICIs. Spatially resolved multi-omics approaches offer valuable insights into potential biomarkers for ICI response and highlight the importance of profiling the TME complexity when developing therapeutic strategies and patient stratification.
Publisher: BMC
Keywords: Humans; *Head and Neck Neoplasms/immunology/drug therapy/pathology; *Immunotherapy; *Tertiary Lymphoid Structures/immunology/pathology; *Tumor Microenvironment/immunology; Proteomics; Squamous Cell Carcinoma of Head and Neck/immunology/drug therapy/pathology; Male; Female; Treatment Outcome; Middle Aged
Research Division(s): Bioinformatics
PubMed ID: 39049036
Publisher's Version: https://doi.org/10.1186/s12967-024-05409-y
Open Access at Publisher's Site: https://doi.org/10.1186/s12967-024-05409-y
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-31 03:30:22

Last Modified: 2024-07-31 03:40:10