Characterization of the Immune Cell Infiltration Landscape in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy

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Abstract

The tumor microenvironment (TME) chiefly consists of tumor cells and tumor-infiltrating immune cells admixed with the stromal component. A recent clinical trial has shown that the tumor immune cell infiltration (ICI) is correlated with the sensitivity to immunotherapy and the head and neck squamous cell carcinoma (HNSC) prognosis. However, to date, the immune infiltrative landscape of HNSC has not yet been elucidated. Herein, we proposed two computational algorithms to unravel the ICI landscape of 1,029 HNSC patients. Three ICI patterns were defined, and the ICI scores were determined by using principal-component analysis. A high ICI score was characterized by an increased tumor mutation burden (TMB) and the immune-activating signaling pathways. Activation of transforming growth factor-β (TGF-β) and WNT signaling pathways were observed in low ICI score subtypes, indicating T cell suppression, and may be responsible for poor prognosis. Two immunotherapy cohorts confirmed patients with higher ICI scores demonstrated significant therapeutic advantages and clinical benefits. This study demonstrated that the ICI scores serve as an effective prognostic biomarker and predictive indicator for immunotherapy. Evaluating the ICI patterns of a larger cohort of samples will extend our understanding of TME, and it may provide directions to the current research investigations on immunotherapeutic strategies for HNSC.

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Abstract

Understanding the tumor-immune microenvironment is critical for improving the efficacy of current immunotherapies. Zhang et al. comprehensively evaluated the cellular, molecular, and genetic factors associated with immune cell infiltration patterns. These have important implications for how tumors respond to immunotherapies and may guide more effective immunotherapy strategies.

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PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.

Michael Curran, Welby Montalvo, Hideo Yagita … (2010)

Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding alphaPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-gamma production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-gamma/TNF-alpha double-producing CD8(+) T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.

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Macrophage regulation of tumor responses to anticancer therapies.

Michele De Palma, Claire Lewis (2013)

Tumor-associated macrophages (TAMs) promote key processes in tumor progression, like angiogenesis, immunosuppression, invasion, and metastasis. Increasing studies have also shown that TAMs can either enhance or antagonize the antitumor efficacy of cytotoxic chemotherapy, cancer-cell targeting antibodies, and immunotherapeutic agents--depending on the type of treatment and tumor model. TAMs also drive reparative mechanisms in tumors after radiotherapy or treatment with vascular-targeting agents. Here, we discuss the biological significance and clinical implications of these findings, with an emphasis on novel approaches that effectively target TAMs to increase the efficacy of such therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

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The head and neck cancer immune landscape and its immunotherapeutic implications.

Rajarsi Mandal, Yasin Senbabaoglu, Alexis Desrichard … (2016)

Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation. We find that both HPV(+) and HPV(-) HNSCC tumors are among the most highly immune-infiltrated cancer types. Strikingly, HNSCC had the highest median Treg/CD8(+) T cell ratio and the highest levels of CD56(dim) NK cell infiltration, in our pan-cancer analysis of the most immune-infiltrated tumors. CD8(+) T cell infiltration and CD56(dim) NK cell infiltration each correlated with superior survival in HNSCC. Tumors harboring genetic smoking signatures had lower immune infiltration and were associated with poorer survival, suggesting these patients may benefit from immune agonist therapy. These findings illuminate the immune landscape of HPV(+) and HPV(-) HNSCC. Additionally, this landscape provides a potentially novel rationale for investigation of agents targeting modulators of Tregs (e.g., CTLA-4, GITR, ICOS, IDO, and VEGFA) and NK cells (e.g., KIR, TIGIT, and 4-1BB) as adjuncts to anti-PD-1 in the treatment of advanced HNSCC.

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Author and article information

Contributors

Boxin Zhang

Journal

Journal ID (nlm-ta): Mol Ther Nucleic Acids

Title: Molecular Therapy. Nucleic Acids

Publisher: American Society of Gene & Cell Therapy

ISSN (Electronic): 2162-2531

Publication date PMC-release: 29 August 2020

Publication date Collection: 04 December 2020

Publication date (Electronic): 29 August 2020

Volume: 22

Pages: 298-309

Affiliations

[1 ]Department of Stomatology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China

[2 ]Oral Research Center of CPLA, Changhai Hospital, Second Military Medical University, 15 Dongjiangwan Road, Shanghai 200081, China

[3 ]Department of Stomatology, Navy Speciality Medical Center of Peoples’ Liberation Army Navy, Shanghai 200052, China

Author notes

[∗ ]Corresponding author: Boxin Zhang, Department of Stomatology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. s441566391@ 123456163.com uczhang01@ 123456163.com

[4]

These authors contributed equally to this work.

Article

Publisher Item ID: S2162-2531(20)30259-6

DOI: 10.1016/j.omtn.2020.08.030

PMC ID: 7522342

PubMed ID: 33230435

SO-VID: 24c24710-5ca7-4fb7-91db-39045ccf2579

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Characterization of the Immune Cell Infiltration Landscape in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy

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Cancer Immunotherapy

Most cited references 16

PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.

Macrophage regulation of tumor responses to anticancer therapies.

The head and neck cancer immune landscape and its immunotherapeutic implications.

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