Background
Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (B
reg
). Recently, we have shown that B
reg
suppress T cell ...function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of B
reg
in head and neck cancer remains unclear.
Methods
Blood (
n
= 42) and tumor tissue (
n
= 39) of head and neck cancer patients and healthy donors (
n
= 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca
2+
influx and ADO production was analyzed in B
reg
and effector B cells (B
eff
) by FACS, luminescence and mass spectrometry. The blockage of the ADO receptor A
2A
was analyzed in a murine head and neck cancer model.
Results
ADO-producing B
reg
were found in tumor tissue and peripheral blood. ADO inhibited the intracellular Bruton’s tyrosine kinase (BTK) and Ca
2+
influx only in B
eff
. The inhibition of BTK by ibrutinib mimicked the effect of ADO, and ibrutinib reduced the production of ADO by downregulation of CD39 in vitro. The inhibition of ADO receptor A
2A
significantly reduced tumor mass and increased B cell infiltration, in vivo.
Conclusion
Our data demonstrate the presence of a novel ADO-producing B
reg
population within the tumor microenvironment in mice and humans. A new model is proposed on how ADO-producing B
reg
can influence the function of B
eff
cells in healthy donors and cancer patients. Thus, the modulation of the ADO pathway in B cells may serve as a therapeutic approach for cancer patients.
Immunotherapeutic agents are nowadays established for treatment of a wide variety of tumor entities, including squamous cell carcinoma of the head and neck region. Originally used in the palliative ...setting, these are increasingly administered with curative intent, e.g., as neoadjuvant treatment. Current research addresses the questions of which patients benefit from the treatment and which combination therapies are successful. The present article summarizes relevant findings of the two international cancer congresses in 2022.
•Liquid biopsy monitoring is feasible in head and neck cancer patients.•Cell-free DNA mutations after surgery identify patients at risk for early relapse.•Increasing variant allele frequencies ...precede clinical progression.
Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific ...mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K
(K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K
was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K
that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K
expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform.
.
This year's American Society of Clinical Oncology (ASCO) meeting included interesting data on first-line therapy of nasopharyngeal carcinomas with PD‑1 inhibitors and on checkpoint inhibition in ...various clinical constellations. At the European Society of Medical Oncology (ESMO) meeting, the results of the CheckMate-651 study were presented.
All abstracts and presentations from the ASCO and ESMO meetings 2021 on immunotherapy in head and neck cancer (HNSCC) were evaluated for their relevance. The most interesting studies are elaborated upon herein.
Studies on locally advanced HNSCC showed an improved response after neoadjuvant pembrolizumab administration. A second cycle did not improve the response rate, but the proportion of patients with a good response was almost doubled. The CheckRad CD8 study showed an improvement in progression-free survival by induction chemoimmunotherapy with tremelimumab and durvalumab followed by stratification according to the CD8 immune cell infiltrate. Two studies were presented on first-line treatment of recurrent/metastatic nasopharyngeal carcinomas. Chemoimmunotherapy showed a higher response rate and prolonged progression-free survival with a similar adverse event profile. In recurrent/metastatic HNSCC, the CheckMate 651 study showed an increased duration of response with nivolumab and ipilimumab and higher response rates than pembrolizumab alone. The primary endpoints for overall survival were not achieved.
PD‑1 inhibition has great potential to change the therapeutic landscape for nasopharyngeal carcinomas in the future. In HNSCC, CD8 tumor infiltrate presents a promising predictive marker for selecting patients who can benefit from radioimmunotherapy. The combination of nivolumab and ipilimumab did not improve overall survival in palliative first-line therapy; thus, no change in the current standard is expected.
Resistance to epidermal growth factor receptor (EGFR)-targeted therapy is insufficiently understood in head and neck squamous cell carcinoma (HNSCC), entailing the lack of predictive biomarkers.Here, ...we studied resistance-mediating EGFR ectodomain and activating RAS mutations by next-generation sequencing (NGS) of cell lines and tumor tissue of cetuximab-naïve patients (46 cases, 12 cell lines), as well as liquid biopsies taken during and after cetuximab/platinum/5-fluorouracil treatment (20 cases). Tumors of cetuximab-naïve patients were unmutated, except for HRAS mutations in 4.3% of patients. Liquid biopsies revealed acquired KRAS, NRAS or HRAS mutations in more than one third of patients after cetuximab exposure. 46% of patients with on-treatment disease progression showed acquired RAS mutations, while no RAS mutations were found in the non-progressive subset of patients, indicating that acquisition of RAS mutant clones correlated significantly with clinical resistance (Chi square p=0.032). The emergence of mutations preceded clinical progression in half of the patients, with a maximum time from mutation detection to clinical progression of 16 weeks.RAS mutations account for acquired resistance to EGFR-targeting in a substantial proportion of HNSCC patients, even though these tumors are rarely mutated at baseline. Liquid biopsies may be used for mutational monitoring to guide treatment decisions.
Immuntherapie von Kopf-Hals-Tumoren Theodoraki, Marie-Nicole; Laban, Simon; Hoffmann, Thomas K.
HNO,
04/2022, Letnik:
70, Številka:
4
Journal Article
Recenzirano
Zusammenfassung
Hintergrund
Beim diesjährigen American Society of Clinical Oncology(ASCO)-Treffen gab es interessante Daten zur Erstlinientherapie nasopharyngealer Karzinome mit PD-1-Inhibitoren und ...zur Checkpointinhibition in verschiedenen klinischen Konstellationen. Beim European Society of Medical Oncology(ESMO)-Meeting wurden die Ergebnisse der CheckMate-651-Studie vorgestellt.
Material und Methoden
Alle Abstracts und Präsentationen der ASCO- und ESMO-Kongresse 2021 zur Immuntherapie von Kopf-Hals-Tumoren (HNSCC) wurden bezüglich Relevanz beurteilt. Die interessantesten Studien wurden aufgearbeitet.
Ergebnisse
Lokal fortgeschrittene HNSCC zeigten ein besseres Ansprechen nach neoadjuvanter Pembrolizumab-Gabe. Die Ansprechrate wurde durch einen zweiten Zyklus nicht erhöht, jedoch wurde der Anteil an Patienten mit stärkerem Ansprechen fast verdoppelt. Die CheckRad-CD8-Studie zeigte eine Verbesserung des progressionsfreien Überlebens durch eine Induktions-Chemoimmuntherapie mit Tremelimumab und Durvalumab sowie Stratifizierung nach dem CD8-Immuninfiltrat. Außerdem wurden Studien zur Erstlinientherapie von rezidivierten/metastasierten Nasopharynxkarzinomen vorgestellt. Eine Chemoimmuntherapie wies eine höhere Ansprechrate bei ähnlichem Nebenwirkungsprofil auf. Bei fortgeschrittenen HNSCC verfehlte die Kombination aus Nivolumab und Ipilimumab die primären Endpunkte für das Gesamtüberleben, wobei die Kombination höhere Ansprechraten im Vergleich zur Pembrolizumab-Monotherapie aufwies.
Schlussfolgerung
Eine PD-1-Inhibition dürfte zukünftig bei der Behandlung des Nasopharynxkarzinoms eine Rolle spielen. Eine CD8-Infiltration des Tumors stellt einen potenziellen prädiktiven Marker zur Auswahl von Patienten dar, die von einer Radioimmuntherapie profitieren könnten. Die Kombination von Nivolumab und Ipilimumab führte zu keiner Verbesserung des Gesamtüberlebens in der palliativen Erstlinientherapie, weshalb hier aktuell keine Zulassungsänderung des bisherigen Standards zu erwarten ist.
Adenosine is a signaling molecule that exerts dual effects on tumor growth: while it inhibits immune cell function and thereby prevents surveillance by the immune system, it influences tumorigenesis ...directly via activation of adenosine receptors on tumor cells at the same time. However, the adenosine‐mediated mechanisms affecting oncogenic processes particularly in head and neck squamous cell carcinomas (HNSCC) are not fully understood. Here, we investigated the role of adenosine receptor activity on HNSCC‐derived cell lines. Targeting the adenosine receptor A2B (ADORA2B) on these cells with the inverse agonist/antagonist PSB‐603 leads to inhibition of cell proliferation, transmigration as well as VEGFA secretion in vitro. At the molecular level, these effects were associated with cell cycle arrest as well as the induction of the apoptotic pathway. In addition, shRNA‐mediated downmodulation of ADORA2B expression caused decreased proliferation. Moreover, in in vivo xenograft experiments, chemical and genetic abrogation of ADORA2B activity impaired tumor growth associated with decreased tumor vascularization. Together, our findings characterize ADORA2B as a crucial player in the maintenance of HNSCC and, therefore, as a potential therapeutic target for HNSCC treatment.
What's new?
The adenosinergic system plays an important role in the development of many types of cancer. However, the underlying mechanisms remain poorly understood. This study set to identify the oncogenic function of the adenosine receptor 2B (ADORA2B) in head and neck squamous cell carcinoma (HNSCC)‐derived tumor cells. The results show that ADORA2B is upregulated and constitutively active in HNSCC‐derived cell lines. This activity is sufficient to promote autonomous cell growth, migration, and angiogenesis in vitro and in vivo. The data suggest ADORA2B as an important biomarker and potential therapeutic target for the treatment of HNSCC and other ADORA2B‐expressing solid tumors.
Influence of Bruton’s Tyrosine Kinase Leichtle, Franziska; Betzler, Annika C; Eizenberger, Carlotta ...
International journal of molecular sciences,
08/2023, Letnik:
24, Številka:
17
Journal Article
Recenzirano
Constitutively active kinases play a crucial role in carcinogenesis, and their inhibition is a common target for molecular tumor therapy. We recently discovered the expression of two oncogenic ...isoforms of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC), Btk-p80 and BTK-p65. However, the precise role of BTK in HNSCC remains unclear. Analyses of a tissue microarray containing benign and malignant as well as inflammatory tissue samples of the head and neck region revealed the preferential expression of BTK-p80 in malignant tissue, whereas BTK-p65 expression was confirmed in over 80% of analyzed metastatic head and neck tumor cases. Therefore, processes associated with metastasis, like cancer stem cell (CSC) enrichment and the epithelial–mesenchymal transition (EMT), which in turn depend on an appropriate cytokine milieu, were analyzed. Treatment of HNSCC-derived cell lines cultured under 3D conditions with the BTK inhibitor AVL-292 caused reduced sphere formation, which was accompanied by reduced numbers of ALDH1A1sup.+ CSCs as well as biological changes associated with the EMT. Moreover, we observed reduced NF-κB expression as well as altered NF-κB dependent pro-tumorigenic and EMT-associated cytokine release of IL-6, IFNγ, and TNFα when BTK activity was dampened. Therefore, an autocrine regulation of the oncogenic BTK-dependent process in HNSCC can be suggested, with BTK inhibition expected to be an effective treatment option for HNSCC.
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