Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck

Hanna, Glenn J.; Liu, Hongye; Jones, Robert E.; Bacay, Alyssa F.; Lizotte, Patrick H.; Ivanova, Elena; Bittinger, Mark; Cavanaugh, Megan E.; Rode, Anja; Schoenfeld, Jonathan D.; Chau, Nicole G.; Haddad, Robert I.; Lorch, Jochen H.; Wong, Kwok‐Kin; Uppaluri, Ravindra; Hammerman, Peter S.

doi:10.1016/j.oraloncology.2017.02.005

Cited by 45 publications

(53 citation statements)

References 35 publications

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“…Supportive of a role of Tregs in driving resistance to treatment are also results from a cross-sectional study showing that in the setting of postoperative chemoradiation, Tregs were increased in frequency and persisted afterwards especially in those with active disease and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC (50). Consistent with these findings, Hanna and colleagues (49), demonstrated a correlation between an inflamed tumor subtype in the recurrent, metastatic squamous cell carcinoma with improved survival compared with a non-inflamed subtype characterized by low CD8 þ T cells, low PD-1/TIM3 coexpression, and higher Tregs.…”

Section: Discussionmentioning

confidence: 69%

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Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

et al. 2019

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Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4-ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell-cell contact, resulting in bidirectional signaling. We found that EphB4-ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8 þ and CD4 þ Foxp3 À T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4-ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4-ephrin-B2 inhibition with RT. In vitro, EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4-ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4-ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy.Significance: These findings present EphB4-ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.

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Section: Discussionmentioning

confidence: 69%

“…The impact of Tregs in HNSCCs has been a controversial topic (47)(48)(49)(50). Although a positive correlation between Tregs and prognosis has been reported in a meta-analysis in HNSCCs (47), it is important to note that the data presented are highly heterogenous and the study only focused on univariate analysis of the results.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

et al. 2019

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“…However, recent observations in melanomas indicate that a relatively low mutational load does not preclude a tumor response to PD1/PD-L1 inhibition [25]. In a recent study, non-synonymous mutational burden did not correlate with response to PD-1 blockade in patients with HNSCC treated by PD-1 blockade [26].…”

Section: Discussionmentioning

confidence: 89%

The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

et al. 2017

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To cite this version:P. Foy, Chloé Bertolus, Marie-Cécile Michallet, Sophie Deneuve, R. Incitti, et al.. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Annals of Oncology, Oxford University Press (OUP), 2017, 28 (8), pp.1934-1941 Background: Never-smokers and never-drinkers patients (NSND) suffering from oral

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“…Ten patient responses (8%) could not be assessed at the time of analysis, as on-treatment imaging was not yet available. Median time to response was 6.2 weeks (range [3][4][5][6][7][8][9][10][11][12][13][14]. There was no difference in the number of responses observed among HPV + /Epstein-Barr virus-positive (EBV + ) and virus-negative patients (7 vs. 10, P = 0.54).…”

Section: Resultsmentioning

confidence: 94%

“…Tumors with a high mutational burden may respond better to immunotherapy, resulting from a diverse genomic landscape driving neoantigen load and favoring immune recognition (6). A T cell-rich or inflamed immunophenotype exists among certain tumors, comprising an interferon γ (IFN-γ) signature and distinct cytokine profile (7) -our own work has shown this among SCCHN tumors (8). While these remain important preliminary observations, they do not currently inform patient selection for checkpoint inhibitor use.…”

Section: Introductionmentioning

confidence: 99%

Frameshift events predict anti–PD-1/L1 response in head and neck cancer

Hanna¹,

Lizotte²,

Cavanaugh³

et al. 2018

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Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.

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Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck

Cited by 45 publications

References 35 publications

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

Frameshift events predict anti–PD-1/L1 response in head and neck cancer

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