Tumor Microenvironment and Immunotherapy Response in Head and Neck Cancer

Abstract

The tumor microenvironment (TME) encompasses cellular and non-cellular components which play an important role in tumor evolution, invasion, and metastasis. A complicated interplay between tumor cells and adjacent TME cells, such as stromal cells, immune cells, inflammatory cells, and cytokines, leads to severe immunosuppression and the proliferation of cancer cells in several solid tumors. An immunosuppressive TME has a significant impact on treatment resistance and may guide response to immunotherapy. In head and neck cancer (HNC), immunotherapeutic drugs have been incorporated in everyday clinical practice. However, despite an exceptional rate of durable responses, only a low percentage of patients respond. In this review, we will focus on the complex interactions occurring in this dynamic system, the TME, which orchestrate key events that lead to tumor progression, immune escape, and resistance. Furthermore, we will summarize current clinical trials that depict the TME as a potential therapeutic target for improved patient selection.

Keywords: cancer-associated fibroblasts; head and neck cancer; immunotherapy; tumor microenvironment; tumor-associated macrophages.

Figure 1

Therapeutic strategies for TME-directed therapy. (A) Targeting TAMs: (1) Anti-CCL2: Monoclonal antibody Carlumab, CCL2 antagonist PF04136309, (2) Anti-CSF1R: Monoclonal Antibody Emactuzumab, tyrosine kinase inhibitor Pexidartinib, (3) TLR agonists: small molecules imiquimod, motolimod, SD-101, (4) CD40 agonists: Monoclonal Antibodies Selicrelumab and CDX-1140, PI3Kγ inhibitor: IPI-549. (B) Targeting MDSCs: (1) IDO inhibitors: Epacadostat, Navoximod, BMS-986205, (2) Anti-CSF1R: Monoclonal Antibody Emactuzumab, tyrosine kinase inhibitor Pexidartinib, (3) CXCR2 inhibitor: SX-682 (4) PDE5 inhibitor tadalafil, (5) STAT3 inhibitor C188-9. (C) Targeting Tregs: (1) GITR agonists: Monoclonal Antibodies MEDI1873 and REGN6569, (2) OX40 agonists: Monoclonal Antibodies MEDI0562, MEDI6469, MEDI6383 and INBRX-106, (3) FOXP3 inhibitor: AZD8701, (4) Anti-CD25: Monoclonal Antibody Daclizumab, (5) Anti-CTLA-4: Monoclonal Antibodies Ipilimumab and Tremelimumab, (6) Anti-CD73: Monoclonal Antbody Oleclumab, (7) Anti-CCR4: Monoclonal Antibody Mogamulizumab. (D) Targeting CAFs: (1) Anti-FAP: Monoclonal Antibodies Sibrotuzumab and RO6874281, (2) STAT3 inhibitor: C188-9, (3) JAK2 inhibitor: Ruxolitinib, (4) Anti-IL-6: Monoclonal Antibody Siltuximab, (5) Anti-MMP: small molecule S-3304. Abbreviations: CAFs = Cancer Associated Fibroblasts, CCR4 = C-C Motif Chemokine Receptor 4,CD73 = Cluster of Differentiation 73, CD40 = Cluster of differentiation 40, CSF1R = Colony stimulating factor, receptor, CTLA-4 = Cytotoxic T Lymphocyte-Associated protein 4,FAP = Fibroblast Activation Protein, FOXP3 = Forkhead box P3, GITR = Glucocorticoid-Induced TNFR-related protein, IDO1 = Indoleamine 2,3-dioxygenase 1, JAK2 = Janus Kinase 2, MDSCs = Myeloid-Derived Suppressor cells, PDE5 = Phosphodiesterase 5, PI3Kγ = Phosphoinositide 3-Kinase γ, STAT3 = Signal transducer and activator of transcription 3, TAMs = Tumor Associated Macrophages, TLR = Toll-like Receptor, Tregs = T regulatory cells.