scholarly journals MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling

2020 ◽  
Vol 3 (6) ◽  
pp. e201900545 ◽  
Author(s):  
Hoi-Lam Ngan ◽  
Yuchen Liu ◽  
Andrew Yuon Fong ◽  
Peony Hiu Yan Poon ◽  
Chun Kit Yeung ◽  
...  
Keyword(s):  
T Cell ◽  
Head And Neck ◽  
Patient Survival ◽  
Mapk Pathway ◽  
Tumor Microenvironments ◽  
Potential Biomarker ◽  
Active Cell Death ◽  
Tumor Mutational Burden ◽  
Erk Activity

MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only “CD8+ T-cell–inflamed” tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3–4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.

scholarly journals Impairment of T-Cell Activation in Head and Neck Cancer In Situ and In Vitro

1999 ◽  
Vol 125 (1) ◽  
pp. 82 ◽  
Author(s):  
Stephan Lang ◽  
Theresa L. Whiteside ◽  
Annette Lebeau ◽  
Reinhard Zeidler ◽  
Brigitte Mack ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
T Cell ◽  
Head And Neck ◽  
T Cell Activation ◽  
Neck Cancer ◽  
Cell Activation

scholarly journals Association between APOBEC3H-Mediated Demethylation and Immune Landscape in Head and Neck Squamous Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Qin Liu ◽  
Yue-wen Luo ◽  
Ruo-yan Cao ◽  
Xue Pan ◽  
Xi-juan Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Head And Neck ◽  
Squamous Carcinoma ◽  
Cd8 T Cell ◽  
Dna Hypomethylation ◽  
Genome Wide ◽  
A Genome ◽  
Potential Biomarker ◽  
Apobec Family

Immunotherapy has been demonstrated as a promising strategy in controlling head and neck squamous cell carcinoma (HNSC). The AID/APOBEC family is well characterized as DNA mutator and considered to play critical roles in immune responses in HNSC. However, the expression pattern and deamination-dependent demethylation roles of AID/APOBECs in HNSC are unclear. In this study, the RNA-seq and DNA methylation profiles of HNSC from TCGA database and cell-based experiments were applied to analyze the relationships between AID/APOBEC expression levels, patients’ clinical outcomes, methylation alterations, and immune responses. Here, we found that APOBEC3H was abnormally upregulated in HNSC patients. HPV+ patients tended to have higher APOBEC3H levels than HPV- patients. Remarkably, patients with high APOBEC3H levels showed a favorable overall survival. Furthermore, tumors with high APOBEC3H levels exhibited a genome-wide DNA hypomethylation pattern. APOBEC3H was identified to demethylate and upregulate CXCL10 and improve CD8+ T cell tumor infiltration in the tumor microenvironment. Collectively, APOBEC3H plays critical roles in CD8+ T cell immune infiltration and activation in HNSC, which may be a potential biomarker for oncoimmunotherapy in HNSC.

scholarly journals Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures

2021 ◽  
Vol 9 (6) ◽  
pp. e002345
Author(s):  
Laurene S Cheung ◽  
Lingling Chen ◽  
Teniola F Oke ◽  
Thomas B Schaffer ◽  
Karim Boudadi ◽  
...  
Keyword(s):  
T Cell ◽  
Head And Neck ◽  
T Cell Infiltration ◽  
Pleomorphic Sarcoma ◽  
Uv Mutation ◽  
Mutational Pattern ◽  
Programmed Death ◽  
Tumor Mutational Burden ◽  
Programmed Death 1 ◽  
Genetic Subgroup

Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.

scholarly journals Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rebekka Duhen ◽  
Carmen Ballesteros-Merino ◽  
Alexandra K. Frye ◽  
Eric Tran ◽  
Venkatesh Rajamanickam ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Primary Endpoint ◽  
Locally Advanced ◽  
Neck Squamous Cell Carcinoma ◽  
Potential Biomarker

AbstractDespite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRβ sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.

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