Immune cell infiltration in head and neck squamous cell carcinoma and patient outcome: a retrospective study

Schneider, Karolin; Marbaix, Étienne; Bouzin, Caroline; Hamoir, Marc; Mahy, Pierre; Bol, Vanessa; Grégoire, Vincent

doi:10.1080/0284186x.2018.1445287

Cited by 46 publications

(53 citation statements)

References 34 publications

(41 reference statements)

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“…T-cell infiltration was associated with a better prognosis in all three of the tumors we examined. This was consistent with prior reports in melanoma and HNSCC 19,60 , but to our knowledge this is a novel finding in GBM that was likely missed by previous studies because T-cells are so rare in GBM.…”

Section: Discussionsupporting

confidence: 93%

Bayesian cell-type deconvolution and gene expression inference reveals tumor-microenvironment interactions

Chu

Danko

2020

Preprint

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Understanding the dynamic interactions between malignant cells and the tumor stroma is a major goal of cancer research. Here we developed a Bayesian model that jointly infers both cellular composition and gene expression in each cell type, including heterogeneous malignant cells, from bulk RNA-seq using scRNA-seq as prior information. We conducted an integrative analysis of 85 single-cell and 1,412 bulk RNA-seq datasets in primary human glioblastoma, head and neck squamous cell carcinoma, and melanoma. We identified cell types correlated with clinical outcomes and explored regional heterogeneity in tumor state and stromal composition. We redefined common molecular subtypes using gene expression in malignant cells, after excluding confounding non-malignant cell types. Finally, we identified genes whose expression in malignant cells correlated with infiltration of macrophages, T-cells, fibroblasts, and endothelial cells across multiple tumor types. Our work provides a new lens that we used to measure cellular composition and expression in a statistically powered cohort of three primary human malignancies. Results Bayesian inference of cell type composition and tumor expressionTED uses a scRNA-seq reference dataset to infer two parameters of interest from bulk RNA-seq data: (i) the proportion of cell types in the bulk population and (ii) the average expression profiles of each cell type. TED describes the proportion and expression profiles of each cell type as latent variables that it infers from the data ( Fig. 1a, Supplementary Fig. 1, Supplementary Note 1). TED makes the key simplifying assumption that each non-malignant cell type shares a common gene expression profile across patients, as observed in the cases analyzed to date 28,30,31 .Critically, each bulk RNA-seq sample is then assumed to have a unique tumor expression profile that we infer from the data.Expression in the reference and bulk RNA-seq data often differ substantially due to batch effects or tumor heterogeneity. To account for uncertainty in the reference cell type expression matrix, TED implements a fully Bayesian inference of tumor composition. First, TED uses Gibbs sampling to estimate the posterior joint distribution of cell type composition, θ0, and gene expression profiles, Z, i.e. P(θ0, Z | φ, X; α) ( Fig. 1a, red, top). Second, to account for tumor cells, or other cell types which cannot be observed in the reference dataset, TED infers a maximum likelihood estimate (MLE) for tumor expression profiles, ψtum (Fig. 1a, red, mid). During this step TED also infers the maximum a posterior estimate (MAP) of the expression profile of non-malignant stromal cells, ψstr, to correct for batch effects between bulk and single cell RNAseq platforms. Last, TED uses the updated expression profile for each patient and cell type to resample the posterior distribution of cell type composition, θ, i.e. P(θ | ψtum , ψstr ,X; α) ( Fig. 1a, red, bottom). Optionally, TED has an additional mode which can be used to learn common patterns of expression heterogeneit...

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Section: Discussionsupporting

confidence: 93%

Bayesian cell-type deconvolution and gene expression inference reveals tumor-microenvironment interactions

Chu

Danko

2020

Preprint

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“…HNSCC generally show a stronger infiltration of immunocompetent cells than most other malignancies, including both various T cell subsets, NK cells, and monocytes [ 94 , 95 , 96 ]. However, the degree of T cell infiltration seems to vary between patients, but for most patients, the infiltrating T cells seem to include a majority of T cells with an effector memory phenotype; the fraction of naïve T cells seems to be decreased, whereas the fractions of various regulatory T cells seems to be increased [ 95 ].…”

Section: Discussionmentioning

confidence: 99%

“…First, strong infiltration of CD3 + T cells has been associated with prolonged survival in several studies; this favorable prognostic impact seems to be mediated especially by CD8 + T cells, but a low frequency of regulatory T cell infiltration may also contribute. A recent study suggested that CD4 + T cells may also contribute to the more favorable prognosis [ 94 , 97 , 98 ]. Second, high infiltration of NK cells has also been associated with a favorable prognosis [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

The Acute Phase Reaction and Its Prognostic Impact in Patients with Head and Neck Squamous Cell Carcinoma: Single Biomarkers Including C-Reactive Protein Versus Biomarker Profiles

et al. 2020

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C-reactive protein (CRP) has a prognostic impact in head and neck squamous cell carcinoma (HNSCC). However, the acute phase reaction involves many other proteins depending on its inducing events, including various cytokines that can function as reaction inducers. In the present study, we compared the pretreatment acute phase cytokine profile for 144 patients with potentially curative HNSCC. We investigated the systemic levels of interleukin (IL)6 family mediators (glycoprotein (gp130), IL6 receptor (R)α, IL6, IL27, IL31, oncostatin M (OSM), ciliary neurotrophic factor (CNTF)), IL1 subfamily members (IL1R antagonist (A), IL33Rα), and tumor necrosis factor (TNF)α. Patient subsets identified from this 10-mediator profile did not differ with regard to disease stage, human papilloma virus (HPV) status, CRP levels, or death cause. Increased CRP, IL6, and IL1RA levels were independent markers for HNSCC-related death in the whole patient population. Furthermore, gp130, IL6Rα, and IL31 were suggested to predict prognosis among tumor HPV-negative patients. Only IL6 predicted survival in HPV-positive patients. Finally, we did a clustering analysis of HPV-negative patients based on six acute phase mediators that showed significant or borderline association with prognosis in Kaplan–Meier analyses; three subsets could then be identified, and they differed in survival (p < 0.001). To conclude, (i) HPV-negative and HPV-positive HNSCC patients show similar variations of their systemic acute phase profiles; (ii) the prognostic impact of single mediators differs between these two patient subsets; and (iii) for HPV-negative patients, acute phase profiling identifies three patient subsets that differ significantly in survival.

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“…Interestingly, EGFR expression is also a prognostic biomarker but not predictive for the efficacy of cetuximab ( 22 ). Many now believe that the antitumoral activity of cetuximab is mainly an immunologic response on the non-human part of the antibody by potentiating the cytotoxic T-cell antitumor immune response, rather than through EGFR-inhibition ( 23 , 24 ). This could explain why trials with fully human EGFR-inhibitors, like panitumumab, have failed to demonstrate any survival benefit compared to or in addition to platinum-based chemotherapy ( 25 ,– 28 ).…”

Section: Changes In Primary (Chemo)radiotherapymentioning

confidence: 99%

“…This could explain why trials with fully human EGFR-inhibitors, like panitumumab, have failed to demonstrate any survival benefit compared to or in addition to platinum-based chemotherapy ( 25 ,– 28 ). HPV+ OPC could potentially benefit more of the enhanced immune response by cetuximab than HPV– OPC since HPV+ OPC contains elevated T- and B-lymphocyte infiltration and expresses viral proteins ( 24 ). To conclude, despite considerable research devoted to this topic, many questions with respect to the use of EGFR-inhibitors and in particular of cetuximab remain unanswered until now.…”

Section: Changes In Primary (Chemo)radiotherapymentioning

confidence: 99%

Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches

2018

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Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) is a distinct clinical entity within the head and neck cancers, with a unique epidemiology and, in general, a favorable prognosis. Because of this favorable prognosis, researchers have considered de-intensifying the current standard treatment of HPV+ OPC in order to reduce acute and late treatment related toxicity without compromising outcome. Current ongoing trials can be divided in three main categories: de-intensification of the chemotherapy by replacing concomitant platinum-based chemotherapy with the EGFR-inhibitor cetuximab, or de-intensification of the radiation dose of either the primary radiotherapy of selected, good-responding patients after induction chemotherapy or of the adjuvant radiotherapy based on pathology features after primary surgery. Despite the good prognosis of the majority of HPV+ OPC patients, a proportion of them still have poor prognosis. This unmet need has led clinical research on new treatment strategies focused on influencing the unique micro-environment of HPV+ OPC with for example immunotherapy. This article summarizes the current understanding regarding the optimal treatment of non-metastatic HPV+ OPC. Ongoing and published clinical trials regarding de-intensification strategies, immunotherapy and proton therapy are described focusing on the rationale and underlying evidence of these emerging treatment strategies. Nevertheless, until the results of the ongoing trials are known, the treatment of HPV+ OPC in clinical practice should remain identical to the treatment of HPV negative OPC.

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Immune cell infiltration in head and neck squamous cell carcinoma and patient outcome: a retrospective study

Abstract: Oropharynx cancer with significant p16 expression showed an increased overall survival and elevated T- and B-lymphocyte infiltration, which suggests a prognostic relevance of immune cell infiltration.

Cited by 46 publications

References 34 publications

Bayesian cell-type deconvolution and gene expression inference reveals tumor-microenvironment interactions

Bayesian cell-type deconvolution and gene expression inference reveals tumor-microenvironment interactions

The Acute Phase Reaction and Its Prognostic Impact in Patients with Head and Neck Squamous Cell Carcinoma: Single Biomarkers Including C-Reactive Protein Versus Biomarker Profiles

Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches

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