scholarly journals CD103+ tumor-resident CD8+ T cell numbers underlie improved patient survival in oropharyngeal squamous cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000452 ◽  
Author(s):  
Rehana Hewavisenti ◽  
Angela Ferguson ◽  
Kevin Wang ◽  
Deanna Jones ◽  
Thomas Gebhardt ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Oropharyngeal Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas

BackgroundHuman Papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is one of the fastest growing cancers in the Western world. When compared to OPSCCs induced by smoking or alcohol, patients with HPV+ OPSCC, have better survival and the mechanisms remain unclear.MethodsThe Cancer Genome Atlas (TCGA) database was examined for genes associated with tissue-resident CD8+ T cells. Multiplex immunohistochemistry (IHC) staining was performed on tumor specimen taken from 35 HPV+ and 27 HPV- OPSCC patients.ResultsTCGA database revealed that the expression of genes encoding CD103 and CD69 were significantly higher in HPV+ head and neck SCCs (HNSCC) than in HPV- HNSCC. Higher expression levels of these two genes were also associated with better overall survival. IHC staining showed that the proportion of CD103+ tumor-resident CD8+ T cells were significantly higher in HPV+ OPSCCs when compared to HPV- OPSCC. This higher level was also associated with both lower risk of loco-regional failure, and better overall survival. Importantly, patients with HPV- OPSCC who had comparable levels of CD103+ tumor-resident CD8+ T cells to those with HPV+ OPSCC demonstrated similar survival as those with HPV+OPSCC.ConclusionOur results show that CD103+ tumor-resident CD8+ T cells are critical for protective immunity in both types of OPSCCs. Our data further suggest that the enhanced local protective immunity provided by tumor-resident T cell responses is the underlying factor driving favorable clinical outcomes in HPV+ OPSCCs over HPV- OPSCCs.

scholarly journals Tumoral HLA Class I and APM Expression and Its Effect on Intratumoral T-cell Reaction and Outcome in HPV-Negative Oral Squamous Cell Carcinoma

2020 ◽  
Author(s):  
Claudia Wickenhauser ◽  
Daniel Bethmann ◽  
Matthias Kappler ◽  
Alexander Walter Eckert ◽  
André Steven ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Hla Class I ◽  
T Cell Infiltration

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance with growing evidence of its underlying molecular mechanisms and its interaction with the immune cell control. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 consecutive human papilloma virus (HPV)-negative OSCC lesions and correlated to tumor specific parameters, the intratumoral immune cell response and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was seen in OSCC sections when compared to non-neoplastic cells. Based on the expression levels of HLA-I APM components three main OSCC subgroups were detected and categorized into HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh phenotypes. In the HLA-Ihigh/APMhigh group, the highest frequency of intratumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3 cells was found. Despite being associated with the highest T cell infiltration, patients within this group presented the most unfavorable survival, which was most evident in stage T2 tumors. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

scholarly journals IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3+ CD8+ T Cells to Drive Squamous Cell Carcinoma Regression

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2131
Author(s):  
Zhen Zeng ◽  
Margaret Veitch ◽  
Gabrielle A. Kelly ◽  
Zewen K. Tuong ◽  
Jazmina G. Cruz ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Infiltration ◽  
Immune Mediated ◽  
Ifn Γ

Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establish and grow in mice immunosuppressed with tacrolimus. When tacrolimus is withdrawn, established SCC tumours subsequently undergo immune-mediated tumour rejection. Through the depletion of individual immune subsets at the time of tacrolimus withdrawal, we established a critical role for CD8+ T cells, but not CD4+ T cells, γδ T cells, or NK cells, in driving the regression of SCC. Regression was critically dependent on IFN-γ, although IFN-γ was not directly cytotoxic to SCC cells. IFN-γ-neutralisation abrogated SCC regression, significantly reduced CD8+ T cell-infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10 and CCL5 within the tumour microenvironment. A strong positive correlation was revealed between CXCL10 expression and CD8+ T cell abundance in tumours. Indeed, blockade of the CXCL10 receptor CXCR3 at the time of tacrolimus withdrawal prevented CD8+ T cell infiltration and the regression of SCC. Chimeric models revealed an important role for immune cells as producers of IFN-γ, but not as recipients of IFN-γ signals via the IFN-γ receptor. Together, these findings suggest a key role for IFN-γ in driving the expression of chemokines within the tumour environment essential for the destruction of established SCC by CD8+ T cells.

scholarly journals Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck

2021 ◽  
Vol 9 (5) ◽  
pp. e002088
Author(s):  
Dan P Zandberg ◽  
Ashley V Menk ◽  
Maria Velez ◽  
Daniel Normolle ◽  
Kristin DePeaux ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Oxidative Metabolism ◽  
Cox Regression ◽  
Tumor Hypoxia ◽  
Parental Line

The majority of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC) (R/M) do not benefit from anti-PD-1 therapy. Hypoxia induced immunosuppression may be a barrier to immunotherapy. Therefore, we examined the metabolic effect of anti-PD-1 therapy in a murine MEER HNSCC model as well as intratumoral hypoxia in R/M patients. In order to characterize the tumor microenvironment in PD-1 resistance, a MEER cell line was created from the parental line that are completely resistant to anti-PD-1. These cell lines were then metabolically profiled using seahorse technology and injected into C57/BL6 mice. After tumor growth, mice were pulsed with pimonidazole and immunofluorescent imaging was performed to analyze hypoxia and T cell infiltration. To validate the preclinical results, we analyzed tissues from R/M patients (n=36) treated with anti-PD-1 mAb, via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs and the percent area (CAIX) and mean intensity (I) of carbonic anhydrase IX in tumor. We analyzed disease control rate (DCR), progression free survival (PFS), and overall survival (OS) using proportional odds and proportional hazards (Cox) regression. We found that anti-PD-1 resistant MEER has significantly higher oxidative metabolism, while there was no difference in glycolytic metabolism. Intratumoral hypoxia was significantly increased and CD8+ T cells decreased in anti-PD-1 resistant tumors compared with parental tumors in the same mouse. In R/M patients, lower tumor hypoxia by CAIX/I was significantly associated with DCR (p=0.007), PFS, and OS, and independently associated with response (p=0.028) and PFS (p=0.04) in a multivariate model including other significant immune factors. During PD-1 resistance, tumor cells developed increased oxidative metabolism leading to increased intratumoral hypoxia and a decrease in CD8+ T cells. Lower tumor hypoxia was independently associated with increased efficacy of anti-PD-1 therapy in patients with R/M HNSCC. To our knowledge this is the first analysis of the effect of hypoxia in this patient population and highlights its importance not only as a predictive biomarker but also as a potential target for therapeutic intervention.

scholarly journals Analysis of radiotherapy‑induced alteration of CD8+ T cells and PD‑L1 expression in patients with uterine cervical squamous cell carcinoma

2021 ◽  
Vol 21 (6) ◽  
Author(s):  
Yasumasa Mori ◽  
Hiro Sato ◽  
Takuya Kumazawa ◽  
Tiara Permata ◽  
Yuya Yoshimoto ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Cervical Squamous Cell Carcinoma

scholarly journals 475 GEN-011–101 (the TiTAN-1 trial): phase 1 study to evaluate the safety, proliferation and persistence of GEN-011, an autologous neoantigen-targeted peripheral T cell therapy in solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A504-A504
Author(s):  
Thomas Davis ◽  
Arthur DeCillis ◽  
Richard Hernandez ◽  
Jessica Price ◽  
Craig Carey ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Phase 1 ◽  
Small Cell ◽  
Small Cell Lung ◽  
Phase 1 Study ◽  
T Cell Therapy

BackgroundGEN-011 is a personalized neoantigen-targeted peripheral blood T cell therapy (NPT) developed for the treatment of adult patients (pts) with solid tumors. The proprietary ATLAS™ (Antigen Lead Acquisition System) will be used to identify true immunogenic neoantigens from each patient‘s tumor mutanome that are recognized by their own CD4+ and/or CD8+ T cells. ATLAS will also identify Inhibigens™, antigen targets of T cells that promote tumor growth.1 Autologous peripheral T cells will be specifically stimulated by up to 30 ATLAS-identified neoantigens, avoiding Inhibigens, to generate an adoptive T cell product. Preliminary data show yields of billions of highly active T cells with 96% neoantigen targeting across 89% of ATLAS selected neoantigens.MethodsTITAN-1 is a multicenter Phase 1 study of GEN-011 NPTs in patients with refractory melanoma, non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), urothelial carcinoma (UC), renal cell carcinoma (RCC), small cell lung cancer (SCLC), cutaneous squamous cell carcinoma (CSCC), and anal squamous cell carcinoma (ASCC). Patients may enter into one of 2 cohorts of 6 DLT-evaluable patients, either a multiple lower dose (MLD) regimen of GEN-011 as an IV infusion at 4-week intervals, up to 5 doses maximum without lymphodepletion, or a single high dose (SHD) regimen of GEN-011 after flu/cy lymphodepletion. Each dose of GEN-011 will be followed by a course of interleukin-2 (IL-2). Patients will be followed for safety, immunogenicity, and anti-tumor activity over approximately a 5-month treatment period. A long-term follow-up will continue through 2 years after the initial dose of GEN-011.Trial Registration clinicaltrials.gov identifier: NCT04596033ReferencesLam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021 March; 11(3):696–713.Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1

scholarly journals Interleukin-6/STAT3 Signaling is Prominent and Associated with Reduced Overall Survival in p16 Negative Oropharyngeal Squamous Cell Carcinoma

2018 ◽  
Vol 13 (3) ◽  
pp. 304-312 ◽  
Author(s):  
Gregory B. Lesinski ◽  
Sreenivas Nannapaneni ◽  
Christopher C. Griffith ◽  
Mihir Patel ◽  
Wanqi Chen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Interleukin 6 ◽  
Oropharyngeal Squamous Cell Carcinoma ◽  
Stat3 Signaling

Potential role of botanical drug APG-157 as immune adjuvant in patients with oral squamous cell carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17572-e17572
Author(s):  
Daniel Sanghoon Shin ◽  
Eri Srivatsan ◽  
Hassan Nasser ◽  
Anela Tosevska ◽  
Jonathan Jacobs ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
Oral Squamous Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Inflammatory Cytokines ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Post Treatment ◽  
Rna Seq

e17572 Background: Natural botanical drugs, such as curcumin, resveratrol and related flavonoids, are under clinical studies. Previous pilot study of curcumin, a polyphenol, for normal and patients with oral squamous cell carcinoma (OSCC) showed significant inhibition of inflammatory cytokines in saliva. Phase I investigation was performed on APG-157 to evaluate the potential utility an as oral drug for the treatment of OSCC. Methods: A double-blind, randomized, placebo-controlled phase I clinical trial was conducted with a botanical preparation containing a combination of curcumin related polyphenol molecules (pharmaceutical name APG-157). 12 Subjects with oral cancer and 13 normal control subjects were recruited. Two doses of the drug, 3x100 mg and 3x200 mg, were tested. The drug was administered orally each hour for 3 consecutive hours. Blood and saliva were collected pre-treatment and 1, 2, 3, and 24 hours post-treatment. Salivary cells and supernatants were analyzed for the expression of cytokines by multiplex ELISA and microbial content by 16S RNA sequence. Pre- and post-treatment tumor biopsies of one subject were studied for expression using the RNA seq and immunofluorescence (IF). Results: This study did not reveal any toxicity and there was a dose dependent inhibition of inflammatory cytokines, IL-1β, TNF-alpha and IL-8 in the salivary supernatant of cancer subjects treated with the drug. Tumor RNA-seq revealed down regulation of gene ontologies of cell adhesion, cell cycle and cell division and up regulation of generation of precursor metabolite/energy in the post-treatment tumor sample. Microbiome study showed significant decrease in Bacterioides after 24 hours of treatment. There was also a trend of decreasing Bacteroides among other cancer subjects treated with APG-157. IF showed a marked increase in the number of CD4, CD8 T cells in post-treatment tumor. PD-L1 expression was up-regulated in the post-treatment tumor sample. Conclusions: APG-157 is found to be safe and toxicity was not observed. The drug has shown a decrease in inflammatory cytokines. Moreover, there was a markedly increased CD4, CD8 T cells infiltration on a subject and decreased Bacteriodes microbial population after APG-157 treatment suggesting that it might have potential synergistic effect with immune checkpoint blockade immunotherapy. Decreased expression of cell growth related genes and increased expression of growth inhibitory genes pointed to a potential anti-tumor activity of APG-157.

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