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'Byrne, K; Warkiani, ME; Ladwa, R; Hughes, BGM; Kulasinghe, A

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'Byrne, K Warkiani, ME Ladwa, R Hughes, BGM Kulasinghe, A

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Publisher:: BMC
Publication Type:: Journal Article
Citation:: J Transl Med, 2024, 22, (1), pp. 677
Issue Date:: 2024-07-24

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Field	Value	Language
dc.contributor.author	Sadeghirad, H
dc.contributor.author	Monkman, J
dc.contributor.author	Tan, CW
dc.contributor.author	Liu, N
dc.contributor.author	Yunis, J
dc.contributor.author	Donovan, ML
dc.contributor.author	Moradi, A
dc.contributor.author	Jhaveri, N
dc.contributor.author	Perry, C
dc.contributor.author	Adams, MN
dc.contributor.author	O'Byrne, K
dc.contributor.author	Warkiani, ME
dc.contributor.author	Ladwa, R
dc.contributor.author	Hughes, BGM
dc.contributor.author	Kulasinghe, A
dc.date.accessioned	2024-08-21T03:48:21Z
dc.date.available	2024-06-17
dc.date.available	2024-08-21T03:48:21Z
dc.date.issued	2024-07-24
dc.identifier.citation	J Transl Med, 2024, 22, (1), pp. 677
dc.identifier.issn	1479-5876
dc.identifier.issn	1479-5876
dc.identifier.uri	http://hdl.handle.net/10453/180447
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	BMC
dc.relation.ispartof	J Transl Med
dc.relation.isbasedon	10.1186/s12967-024-05409-y
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	11 Medical and Health Sciences
dc.subject.classification	Immunology
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.classification	42 Health sciences
dc.subject.mesh	Humans
dc.subject.mesh	Head and Neck Neoplasms
dc.subject.mesh	Immunotherapy
dc.subject.mesh	Tertiary Lymphoid Structures
dc.subject.mesh	Tumor Microenvironment
dc.subject.mesh	Proteomics
dc.subject.mesh	Squamous Cell Carcinoma of Head and Neck
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Middle Aged
dc.subject.mesh	Humans
dc.subject.mesh	Head and Neck Neoplasms
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Immunotherapy
dc.subject.mesh	Proteomics
dc.subject.mesh	Middle Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Tumor Microenvironment
dc.subject.mesh	Tertiary Lymphoid Structures
dc.subject.mesh	Squamous Cell Carcinoma of Head and Neck
dc.subject.mesh	Humans
dc.subject.mesh	Head and Neck Neoplasms
dc.subject.mesh	Immunotherapy
dc.subject.mesh	Tertiary Lymphoid Structures
dc.subject.mesh	Tumor Microenvironment
dc.subject.mesh	Proteomics
dc.subject.mesh	Squamous Cell Carcinoma of Head and Neck
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Middle Aged
dc.title	Spatial dynamics of tertiary lymphoid aggregates in head and neck cancer: insights into immunotherapy response.
dc.type	Journal Article
utslib.citation.volume	22
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/All Manual Groups
pubs.organisational-group	University of Technology Sydney/All Manual Groups/Centre for Health Technologies (CHT)
pubs.organisational-group	University of Technology Sydney/All Manual Groups/Institute of Biomedical Materials and Devices (IBMD)
pubs.organisational-group	University of Technology Sydney/All Manual Groups/Institute of Biomedical Materials and Devices (IBMD)/Associate Member
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-08-21T03:48:12Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	22
utslib.citation.issue	1

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.

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