IL1 Pathway in HPV-Negative HNSCC Cells Is an Indicator of Radioresistance After Photon and Carbon Ion Irradiation Without Functional Involvement

Abstract

BackgroundTreatment of locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) with photon radiation is the standard of care but shows only moderate success. Alterations in response toward DNA DSB repair, apoptosis, and senescence are underlying determinants of radioresistance in the tumor cells. Recently, senescence and the associated secretory phenotype (SASP) came into the focus of research and raised the need to identify the tumor-promoting molecular mechanisms of the SASP. The aim of this project was to unravel more of this process and to understand the impact of the IL1 pathway, which plays a major role in SASP. The studies were performed for photon and 12C-ion irradiation, which strongly vary in their effect on radioresistance.Materials and MethodsA panel of five HPV-negative HNSCC cell lines was treated with photon and 12C-ion irradiation and examined for clonogenic survival, DNA DSB repair, and senescence. SASP and IL1 gene expressions were determined by RNA sequencing and activation of the IL1 pathway by ELISA. A functional impact of IL1A and IL1B was examined by specific siRNA knockdown.ResultsCell killing and residual DSBs were higher after 12C-ion than after photon irradiation. 12C-ion induced more senescence with a significant correlation with cell survival. The impact on radioresistance appears to be less than after photon irradiation. The expression of SASP-related genes and the IL1 pathway are strongly induced by both types of irradiation and correlate with radioresistance and senescence, especially IL1A and IL1B which exhibit excellent associations. Surprisingly, knockdown of IL1A and IL1B revealed that the IL1 pathway is functionally not involved in radioresistance, DSB repair, or induction of senescence.ConclusionsIL1A and IL1B are excellent indicators of cellular radioresistance and senescence in HNSCC cells without functional involvement in these processes. Clearly more research is needed to understand the molecular mechanisms of senescence and SASP and its impact on radioresistance.

Senescence in head and neck squamous cell carcinoma: relationship between senescence-associated secretory phenotype (SASP) mRNA expression level and clinicopathological features

“…IL1b is increased in a variety of malignancies, and it is well recognized that patients with overproduction of IL1b have poorer prognosis. Also, it has been demonstrated that IL1b is an indicator of cellular radioresistance and senescence in HNSCC cells without functional involvement in these processes [ 16 ]. In our study we saw a higher IL1b transcript level in both age groups (≤ 60 and > 60) and locations (larynx and oral cavity) in men but not women, in all histologic grade stages (G1-G3) and T3-T4 and N0, N2 TNM tumor stages.…”

Lumican is a potential predictor on the efficacy of concurrent chemoradiotherapy in cervical squamous cell carcinoma

“…IL1B can promote tumor-promoting inflammation in breast cancer, and it can be targeted in metastatic breast cancer patients with a soluble IL1 receptor antagonist, and also can be an immunomodulatory target in treatment-resistant breast cancer [ 52 ]. IL1 pathway is strongly induced by irradiation and correlate with radioresistance and senescence, especially IL1A and IL1B which exhibit excellent associations [ 53 ]. Our cell-cell communication network identified a strong association of the IL1 pathway with the macrophages, suggesting that the IL1 pathway might be involved in CESC CCRT resistance.…”

Organization and operation of multi particle therapy facilities: the Marburg Ion-Beam Therapy Center, Germany (MIT)

“…nasal cavity, ear) [12] or in second-line treatment [16][17][18] with good clinical results that argue for a broader clinical practice. Moreover, the multifaceted mechanisms of therapy resistance, exhibited by HNSCC tumors, such as inflammatory and immune-modulating cytokine and chemokine signaling or overstimulation of the PI3K/AKT/TOR signaling pathway are alleviated for carbon ion irradiation [19,20]. In this context, [15] is a valuable source to plan further clinical studies.…”