Pre‐treatment <scp>CD</scp>8<sup>+</sup> tumour‐infiltrating lymphocyte density predicts distant metastasis after definitive treatment in patients with stage <scp>III</scp>/<scp>IV</scp> hypopharyngeal squamous cell carcinoma

Ono, Takeharu; Azuma, Koichi; Kawahara, Akihiko; Akiba, Jun; Kakuma, Tatsuyuki; Chitose, Shun‐ichi; Umeno, Hirohito

doi:10.1111/coa.13171

Cited by 14 publications

(17 citation statements)

References 23 publications

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“…Immunohistochemically (IHC) determined high CD8 + T-cell counts are associated with good prognosis in postoperative chemo-radiotherapy treated patients, further indicating its relevance for HNSCC (57). A good prognosis association with IHC CD8 + TIL density was found in patients with oropharyngeal squamous cell carcinoma treated with surgery or (chemo) radiotherapy and in a similarly mixed treatment cohort of hypopharyngeal SCC patients (58)(59)(60).…”

Section: Introductionmentioning

confidence: 90%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8 + T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). van der Heijden et al. HNSCC Biology Impacting Chemo-Radiotherapy Outcomes Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8 + T-cells: HR = 2.2, p < 0.05; CD8 + T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8 + Tcell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.

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Section: Introductionmentioning

confidence: 90%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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“…Hypopharyngeal squamous cell carcinoma (HPSCC) is a highly malignant type of head and neck cancer, which is the eighth most common cancer worldwide [1]. Although its incidence is comparatively low, HPSCC is usually diagnosed at an advanced stage due to unapparent early symptoms [2] . Although there are many treatments, such as surgery, concurrent chemoradiation therapy (CCRT) and radiation therapy, the five-year survival rate is less than 35% [3,4].…”

Section: Introductionmentioning

confidence: 99%

The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma

et al. 2020

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Background: Cancer cells induce the infiltration of various immune cells that are located or distributed in different sites and play multiple roles, which have recently been proposed to predict clinical outcomes. We therefore studied the prognostic significance of the presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different types of immune cells in hypopharyngeal squamous cell carcinoma (HPSCC). Methods: We retrospectively analysed 132 consecutive patients diagnosed with advanced HPSCC in 2013-2017. Tumoural parenchyma was immunohistochemically counted manually for the number of CD8, CD4 and Foxp3 cells. The ratios of CD8/Foxp3 and CD8/CD4 ratios were calculated for each specimen and analyzed with respect to patient clinicopathological variables and prognosis. Results: HPSCC patients with high levels of TILs showed evident correlations with well differentiated tumors (P < 0.05). Moreover, Foxp3+ TIL is also associated with overall staging group and T category (P = 0.048 and P = 0.046, respectively). Kaplan-Meier analysis showed that high CD8 and FoxP3 infiltration correlated with favourable overall survival (OS, P = 0.019 and P = 0.001), disease-free survival (DFS, P = 0.045 and P = 0.028) and distant metastasis-free survival (DMFS, P = 0.034 and P = 0.009), respectively, but only Foxp3 displayed prognostic significance for DMFS in multivariate analysis (MVA). In the lymphocyte ratio analysis, CD8/Foxp3 appeared to play a pivotal role, and patients with a high CD8/Foxp3 ratio had a superior 3-year DFS and DMFS compared with those a low CD8/Foxp3 ratio in both univariate analysis (UVA) and MVA (P = 0.015 and P = 0.011). A high CD8/CD4 ratio was associated with better DFS and local relapse-free survival (LRFS) in UVA, and was an independent prognostic factor for improved LRFS in MVA (P = 0.040).

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“…3,[7][8][9] Although several studies have shown that CD8 + T cells might play an important role in subsets of immune cells, and that HNC patients with higher preexisting CD8+TIL density had more favorable prognosis than those without, there are few reports on the association between locoregional control by RT or CRT and CD8 + TIL density. [10][11][12] Gerber et al reported that the interferon-gamma-mediated immune system is required for effective RT and that elimination of CD8 + cells decreases the antitumor effects of RT. 13 However, some reports have failed to show significant association between CD8+TIL density and locoregional control.…”

Section: Introductionmentioning

confidence: 99%

Predictive value of CD8/FOXP3 ratio combined with PD‐L1 expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy

et al. 2020

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Background: Little is known about immune-related radiosensitivity in patients with squamous cell carcinoma of the larynx (SCC-L) treated with radiation therapy (RT). Methods: We retrospectively reviewed 91 patients with SCC-L treated with RT or chemoradiation therapy and performed immunohistochemical examination to analyze PD-L1 level on tumor cells, CD4 + tumor-infiltrating lymphocytes (TILs), CD8 + TIL, and FOXP3 + TIL using pretreated biopsy specimens. The association between these immune-related parameters and radiosensitivity was evaluated. Results: Multivariate analyses showed that high CD8/FOXP3 ratio combined with negative PD-L1 expression was an independent and significant favorable predictive factor for local control, compared with the other groups. Conclusions: We showed that high CD8/FOXP3 ratio combined with negative PD-L1 expression might be a useful biomarker of radiosensitivity in patients with SCC-L receiving definitive RT. We propose that coassessment of CD8/FOXP3 ratio and PD-L1 expression level in tumor cells can help predict potential radiosensitivity in patients with SCC-L.

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Pre‐treatment CD8⁺ tumour‐infiltrating lymphocyte density predicts distant metastasis after definitive treatment in patients with stage III/IV hypopharyngeal squamous cell carcinoma

Abstract: Higher pre-treatment CD8 tumour-infiltrating lymphocyte density is a useful predictive biomarker for reduced distant metastasis and better prognosis.

Cited by 14 publications

References 23 publications

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma

Predictive value of CD8/FOXP3 ratio combined with PD‐L1 expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy

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Pre‐treatment CD8+ tumour‐infiltrating lymphocyte density predicts distant metastasis after definitive treatment in patients with stage III/IV hypopharyngeal squamous cell carcinoma

Abstract: Higher pre-treatment CD8 tumour-infiltrating lymphocyte density is a useful predictive biomarker for reduced distant metastasis and better prognosis.

Cited by 14 publications

References 23 publications

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma

Predictive value of CD8/FOXP3 ratio combined with PD‐L1 expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy

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Pre‐treatment CD8⁺ tumour‐infiltrating lymphocyte density predicts distant metastasis after definitive treatment in patients with stage III/IV hypopharyngeal squamous cell carcinoma