Systemic immune activation coexists with compartment-specific regulatory enrichment in matched blood, peritumor, and tumor tissue from advanced oral squamous cell carcinoma
6 affiliations
- 1Translational Immuno-Oncology Group, International Research Center, A.C.Camargo Cancer Center , , ,
- 2Translational Immuno-Oncology Laboratory, Faculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein , , ,
- 3Center for Research in Immuno-Oncology (CRIO), Faculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein , , ,
- 4International Research Center, A.C.Camargo Cancer Center , , ,
- 5Medical Oncology Department, Head and Neck Cancer Reference Center, A.C.Camargo Cancer Center , , ,
- 6Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center , , ,
Abstract
Background: Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral cancer and is characterized by a poor prognosis and frequent immune evasion. While the tumor microenvironment (TME) plays a central role in modulating responses to therapy, its relationship with systemic immune signatures remains poorly understood.
Methods: We performed high-dimensional immune profiling in matched peripheral blood, adjacent non-neoplastic peritumor mucosa, and tumor tissue from Human Papillomavirus (HPV)-negative, treatment-naïve patients with advanced OSCC. Soluble mediators were quantified by multiplex immunoassay, and immune cell phenotypes were assessed by multiparametric flow cytometry. Compartment-specific patterns were evaluated using paired and unpaired comparisons, dimensionality reduction, ordinal trend analysis, unsupervised clustering, and correlation networks.
Results: Seventeen plasma mediators were significantly elevated in OSCC patients compared with healthy donors. Paired cellular profiling identified compartment-specific differences across blood, peritumor and tumor, and selected PD-1 ⁺ CD95 ⁺ , CD25 ⁺ FoxP3 ⁺ , and PD-L1 ⁺ populations showed significant progressive trends along the blood-peritumor-tumor axis. CD4 ⁺ mucosal-associated invariant T (MAIT)-like cells (TCR Vα7.2 ⁺ CD161 ⁺ ) were relatively enriched in peritumor tissue, but the peritumor compartment was not uniformly intermediate across all populations. Correlation networks showed limited overlaps, with greater overlap between peritumor and tumor networks than between either tissue compartment and blood. Plasma profiling showed elevated pro-inflammatory cytokines, chemokines, and growth factors, consistent with systemic immune activation. Peripheral blood exhibited an activated phenotype with increased frequencies of activated T and NK cells, alongside CD4 ⁻ CD8 ⁻ TCR Vα7.2 ⁺ CD161 ⁺ cells. In contrast, the tumor microenvironment was enriched for CD95 ⁺ PD-1 ⁺ CD4 ⁺ and CD8 ⁺ T cells, NK cells and PD-L1 ⁺ monocytes and CD4 ⁺ MAIT-like cells. The peritumor compartment showed a distinct immune profile marked by regulatory T cell accumulation and other immunosuppressive mediators, rather than a uniform intermediate state between blood and tumor. Correlation networks revealed pronounced shifts in immune coordination across compartments.
Conclusions: Advanced OSCC is associated with distinct systemic and tissue immune profiles. These exploratory findings identify compartment-specific immune features and selected monotonic trends that warrant future spatial, functional, and clinical validation.
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BibTeX
@article{galdino2026systemic,
title = {{Systemic immune activation coexists with compartment-specific regulatory enrichment in matched blood, peritumor, and tumor tissue from advanced oral squamous cell carcinoma}},
author = {Nayane Alves de Lima Galdino and Flávio Pignataro-Oshiro and João Figueira Scarini and Raísa Sales de Sá and Guilherme Ferreira de Britto Evangelista and Amanda Braga Figueiredo and Clara Maciel Cavalcanti and Katia Luciano Pereira Morais and Vanessa Alves Gasparini and Hugo Fontan Kohler and Thiago Bueno de Oliveira and Luiz Paulo Kowalski and Kenneth J. Gollob},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1923358},
url = {https://europepmc.org/article/PMC/PMC13669159},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systemic immune activation coexists with compartment-specific regulatory enrichment in matched blood, peritumor, and tumor tissue from advanced oral squamous cell carcinoma
AU - Nayane Alves de Lima Galdino
AU - Flávio Pignataro-Oshiro
AU - João Figueira Scarini
AU - Raísa Sales de Sá
AU - Guilherme Ferreira de Britto Evangelista
AU - Amanda Braga Figueiredo
AU - Clara Maciel Cavalcanti
AU - Katia Luciano Pereira Morais
AU - Vanessa Alves Gasparini
AU - Hugo Fontan Kohler
AU - Thiago Bueno de Oliveira
AU - Luiz Paulo Kowalski
AU - Kenneth J. Gollob
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1923358
UR - https://europepmc.org/article/PMC/PMC13669159
AB - Background: Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral cancer and is characterized by a poor prognosis and frequent immune evasion. While the tumor microenvironment (TME) plays a central role in modulating responses to therapy, its relationship with systemic immune signatures remains poorly understood. Methods: We performed high-dimensional immune profiling in matched peripheral blood, adjacent non-neoplastic peritumor mucosa, and tumor tissue from Human Papillomavirus (HPV)-negative, treatment-naïve patients with advanced OSCC. Soluble mediators were quantified by multiplex immunoassay, and immune cell phenotypes were assessed by multiparametric flow cytometry. Compartment-specific patterns were evaluated using paired and unpaired comparisons, dimensionality reduction, ordinal trend analysis, unsupervised clustering, and correlation networks. Results: Seventeen plasma mediators were significantly elevated in OSCC patients compared with healthy donors. Paired cellular profiling identified compartment-specific differences across blood, peritumor and tumor, and selected PD-1 ⁺ CD95 ⁺ , CD25 ⁺ FoxP3 ⁺ , and PD-L1 ⁺ populations showed significant progressive trends along the blood-peritumor-tumor axis. CD4 ⁺ mucosal-associated invariant T (MAIT)-like cells (TCR Vα7.2 ⁺ CD161 ⁺ ) were relatively enriched in peritumor tissue, but the peritumor compartment was not uniformly intermediate across all populations. Correlation networks showed limited overlaps, with greater overlap between peritumor and tumor networks than between either tissue compartment and blood. Plasma profiling showed elevated pro-inflammatory cytokines, chemokines, and growth factors, consistent with systemic immune activation. Peripheral blood exhibited an activated phenotype with increased frequencies of activated T and NK cells, alongside CD4 ⁻ CD8 ⁻ TCR Vα7.2 ⁺ CD161 ⁺ cells. In contrast, the tumor microenvironment was enriched for CD95 ⁺ PD-1 ⁺ CD4 ⁺ and CD8 ⁺ T cells, NK cells and PD-L1 ⁺ monocytes and CD4 ⁺ MAIT-like cells. The peritumor compartment showed a distinct immune profile marked by regulatory T cell accumulation and other immunosuppressive mediators, rather than a uniform intermediate state between blood and tumor. Correlation networks revealed pronounced shifts in immune coordination across compartments. Conclusions: Advanced OSCC is associated with distinct systemic and tissue immune profiles. These exploratory findings identify compartment-specific immune features and selected monotonic trends that warrant future spatial, functional, and clinical validation.
SN - 1664-3224
ER -