Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti–PD-1 in head and neck cancer

Science Immunology, Год журнала: 2023, Номер 8(87)

Опубликована: Сен. 8, 2023

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration anti-programmed death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the microenvironment (TME). However, mechanisms underlying dynamics antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, approaches to increase are lacking. In a phase 2 trial (NCT02296684), we observed that 45% treated two doses pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis 17,158 CD8

Язык: Английский

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Compartmentalized spatial profiling of the tumor microenvironment in head and neck squamous cell carcinoma identifies immune checkpoint molecules and tumor necrosis factor receptor superfamily members as biomarkers of response to immunotherapy

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Апрель 3, 2023

Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in recurrent or metastatic (R/M) disease, however, only a subset benefit from immunotherapy. Studies implicated tumor microenvironment (TME) HNSCC as major factor therapy response, highlighting need to better understand TME, particularly by spatially resolved means determine cellular molecular components. Here, we employed targeted spatial profiling proteins on cohort pre-treatment tissues R/M disease identify novel biomarkers response within stromal margins. By grouping patient outcome categories into non-response, based Response Evaluation Criteria Solid Tumors (RECIST) show that immune molecules, including PD-L1, B7-H3, VISTA, were differentially expressed. Patient responders possessed significantly higher expression PD-L1 but lower VISTA. Analysis subgroups indicated necrosis receptor (TNFR) superfamily members OX40L, CD27, 4-1BB, CD40, CD95/Fas, associated immunotherapy outcome. CD40 was patient-responders than non responders, while CD95/Fas partial (PR) relative those stable (SD) progressive (PD). Furthermore, found high 4-1BB compartment, not stroma, overall survival (OS) (HR= 0.28, p-adjusted= 0.040). Moreover, regions 0.27, 0.035), CD27 stroma 0.2, p-adjusted=0.032) outcomes. Taken together, this study supports role molecules implicates TNFR key players our HNSCC. Validation these findings prospective is required robustness tissue signatures.

Язык: Английский

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Deciphering head and neck cancer microenvironment: Single‐cell and spatial transcriptomics reveals human papillomavirus‐associated differences

Journal of Medical Virology, Год журнала: 2024, Номер 96(1)

Опубликована: Янв. 1, 2024

Abstract Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), the incidence HPV ‐ associated HNSCC increasing. The role tumor microenvironment in viral infection metastasis needs to be explored further. We studied molecular characteristics primary tumors (PTs) lymph node metastatic (LNMTs) by stratifying them based on their status. Eight samples for single‐cell RNA profiling six spatial transcriptomics (ST), composed matched (PT) metastases (LNMT), were collected from both negative (HPV − ) HPV‐positive + patients. Using 10x Genomics Visium platform, integrative analyses with sequencing performed. Intracellular intercellular alterations analyzed, findings confirmed using experimental validation publicly available data set. tissues substantial amount lymphoid cells regardless presence or absence metastasis, whereas tissue exhibited remarkable changes number macrophages plasma cells, particularly LNMT. From ST set, we discovered central gene, pyruvate kinase muscle isoform 1/2 ( PKM2 ), which closely stemness cancer stem cell‐like populations LNMT tissue. consistent expression was observed line knockdown weakened spheroid formation ability. Furthermore, found an ectopic structure morphology clinical effects slide patients verified immunohistochemistry. Finally, ephrin‐A (EPHA2) pathway detected as important signals angiogenesis profiles, EPHA2 declined migration. Our study described distinct cellular composition sites These results provide insights into biology context its potential implications.

Язык: Английский

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The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

Cancers, Год журнала: 2023, Номер 15(6), С. 1642 - 1642

Опубликована: Март 7, 2023

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive heterogeneous groups human neoplasms. HNSCC characterized by high morbidity, accounting for 3% all cancers, mortality with ~1.5% cancer deaths. It was common worldwide in 2020, according to latest GLOBOCAN data, representing seventh prevalent malignancy. Despite great advances surgical techniques application modern combinations cytotoxic therapies, remains a leading cause death low overall survival rate not exceeding 40-60% patient population. The causes patients are its frequent nodal metastases local neoplastic recurrences, as well relatively response treatment severe drug resistance. Much evidence suggests that tumour microenvironment (TME), infiltrating lymphocytes (TILs) circulating various subpopulations immunocompetent cells, such regulatory T cells (CD4

Язык: Английский

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Immune cell topography of head and neck cancer

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(7), С. e009550 - e009550

Опубликована: Июль 1, 2024

Background Approximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are options for recurrent/metastatic HNSCC; however, less than 20% patients respond. To increase this response rate, it is fundamental to our understanding the spatial tumor immune microenvironment (TIME). Methods In total, 53 HNSCC specimens were included. Using a seven-color multiplex immunohistochemistry panel we identified cells, CD163+macrophages, B CD8+T CD4+T helper cells regulatory T (Tregs) in treatment-naive surgical resection (n=29) biopsies (n=18). further characterize tumor-infiltrating stained (n=12) five-color tumor-resident including CD103, Ki67, CD8 pan-cytokeratin. Secretome analysis was performed on matched suspensions (n=11) measure protein levels. Results Based infiltrates, four different immunotypes: fully infiltrated, stroma-restricted, immune-excluded, immune-desert. We found higher cytokine levels infiltrated tumors compared other immunotypes. While highest infiltrates observed invasive margin all CD163+macrophages Tregs had tendency infiltrate center. Within center, especially stayed at stroma, whereas followed by more often localized within fields. Also, away from formed aggregates while tended be closely located each other. Across various anatomical sites neck, oral cavity exhibited densities Tregs. Moreover, distance shortest carcinoma (OCSCC), suggesting interaction between lymphocytes cells. fraction 10 µm lowest OCSCC, indicating fewer myeloid/T-cell suppressive interactions OCSCC. Conclusions comprehensively described TIME using unique data set specimens. discovered that composition, as well relative localization TIME, differed distinct neck.

Язык: Английский

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Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma and the Immune System: Pathogenesis, Immunotherapy and Future Perspectives

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2798 - 2798

Опубликована: Фев. 28, 2024

Oropharyngeal squamous cell carcinoma (OPSCC), a subset of head and neck (HNSCC), involves the palatine tonsils, soft palate, base tongue, uvula, with ability to spread adjacent subsites. Personalized treatment strategies for Human Papillomavirus-associated oropharynx (HPV+OPSCC) are yet be established. In this article, we summarise our current understanding pathogenesis HPV+OPSCC, intrinsic role immune system, ICI clinical trials, potential small molecule immunotherapy in HPV+OPSCC.

Язык: Английский

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Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Март 12, 2024

Abstract Background While T cell-activating immunotherapies against recurrent head and neck squamous cell carcinoma (HNSCC) have shown impressive results in clinical trials, they are often ineffective the majority of patients. NK cells potential targets for immunotherapeutic intervention; however, setback monalizumab-based therapy HNSCC highlights need an alternative treatment to enhance their antitumor activity. Methods Single-cell RNA sequencing (scRNA-seq) TCGA datasets were used identify key molecular alterations cells. Representative HPV-positive ( +) HPV-negative − ) lines orthotopic mouse models validate bioinformatic findings. Changes immune examined by flow cytometry immunofluorescence. Results Through integration scRNA-seq data with data, we found that impact IL6/IL6R CCL2/CCR2 signaling pathways on evasion attack is more pronounced HPV cohort compared + cohort. In models, blocking IL6 a neutralizing antibody suppressed but not tumors, which was accompanied increased tumor infiltration proliferation CD161 Notably, combining CCR2 chemokine receptor antagonist RS504393 blockade resulted effect associated activated intratumoral either agent alone. Conclusions These findings demonstrate dual effectively enhances activity HNSCC, providing novel strategy treating this type cancer.

Язык: Английский

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Artificial Intelligence Applications in Oral Cancer and Oral Dysplasia

Tissue Engineering Part A, Год журнала: 2024, Номер 30(19-20), С. 640 - 651

Опубликована: Июль 23, 2024

Oral squamous cell carcinoma (OSCC) is a highly unpredictable disease with devastating mortality rates that have not changed over the past decades, in face of advancements treatments and biomarkers, which improved survival for other cancers. Delays diagnosis are frequent, leading to more disfiguring poor outcomes patients. The clinical challenge lies identifying those patients at highest risk developing OSCC. epithelial dysplasia (OED) precursor OSCC variable behavior across There no reliable clinical, pathological, histological, or molecular biomarker determine individual OED Similarly, there robust biomarkers predict treatment This review aims highlight artificial intelligence (AI)-based methods develop predictive transformation response. Biomarkers such as S100A7 demonstrate promising appraisal malignant OED. Machine learning-enhanced multiplex immunohistochemistry workflows examine immune patterns organization within tumor microenvironment generate outcome predictions immunotherapy. Deep learning (DL) an AI-based method using extended neural network related architecture multiple "hidden" layers simulated neurons combine simple visual features into complex patterns. DL-based digital pathology currently being developed assess outcomes. integration machine epigenomics epigenetic modification diseases improve our ability detect, classify, associated marks. Collectively, these tools showcase discovery technology, may provide potential solution addressing current limitations predicting behavior, both challenges must be addressed order survival.

Язык: Английский

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The current role of dendritic cells in the progression and treatment of colorectal cancer

Cancer Biology and Medicine, Год журнала: 2024, Номер unknown, С. 1 - 15

Опубликована: Авг. 22, 2024

Colorectal cancer (CRC) is the third most common and second leading cause of cancer-related deaths worldwide. Dendritic cells (DCs) constitute a heterogeneous group antigen-presenting that are important for initiating regulating both innate adaptive immune responses. As crucial component system, DCs have pivotal role in pathogenesis clinical treatment CRC. cross-present tumor-related antigens to activate T trigger an antitumor response. However, function impaired tolerance promoted due presence tumor microenvironment. This review systematically elucidates specific characteristics functions different DC subsets, as well play response within CRC Moreover, how contribute progression potential therapies enhance immunity on basis existing data also discussed, which will provide new perspectives approaches immunotherapy patients with

Язык: Английский

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Rising Trend in the Prevalence of HPV-Driven Oropharyngeal Squamous Cell Carcinoma during 2000–2022 in Northeastern Italy: Implication for Using p16INK4a as a Surrogate Marker for HPV-Driven Carcinogenesis

Cancers, Год журнала: 2023, Номер 15(9), С. 2643 - 2643

Опубликована: Май 7, 2023

The prevalence and incidence of oropharyngeal squamous cell carcinomas (OPSCCs) driven by human papillomavirus (HPV) infection are increasing worldwide, being higher in high-income countries. However, data from Italy scanty. p16INK4a overexpression is the standard determining HPV-driven carcinogenesis, but disease impacts on its positive predictive value.This a multicenter retrospective study enrolling 390 consecutive patients aged ≥18 years, diagnosed with pathologically confirmed OPSCC Northeastern between 2000 2022. High-risk HPV-DNA status were retrieved medical records or evaluated formalin-fixed paraffin-embedded specimens. A tumor was defined as when double for high-risk overexpression.Overall, 125 cases (32%) HPV-driven, significant upward temporal trend 12% 2000-2006 to 50% 2019-2022. cancer tonsil base tongue increased up 59%, whereas it remained below 10% other subsites. Consequently, value 89% former 29% latter.The continued increase, even most recent period. When using surrogate marker transforming HPV infection, each institution should consider subsite-specific rates these significantly impact value.

Язык: Английский

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