Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer
R. Bryan Bell, Michael Gough, Marka Crittenden, Kristina Young
R. Bryan Bell, Michael Gough, Marka Crittenden, Kristina Young
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Commentary

Moving beyond the T cell synapse for combination neoadjuvant immunotherapy in head and neck cancer

Abstract

Patients with HPV-unrelated head and neck squamous cell carcinoma (HPV-unrelated HNSCC) show only modest benefit from treatment with PD-1 inhibitors (PD-1i). Targeting transforming growth factor β (TGF-β) may make PD-1i more effective by inducing T cell responses. In this issue of the JCI, Redman et al. performed a clinical trial in 14 patients with HPV-unrelated HNSCC using bintrafusp alfa, a bifunctional fusion protein that blocks PD-L1 and TGF-β. Primary tumors displayed pathologic responses with 5 of 14 patients having at least a partial response. While no primary tumor or metastatic lymph node demonstrated a complete pathologic response, the findings suggest that concurrent neoadjuvant inhibition of PD-L1 and TGF-β may provide a rational strategy to improve pathologic response and clinical outcome in patients with HPV-unrelated HNSCC.

Authors

R. Bryan Bell, Michael Gough, Marka Crittenden, Kristina Young

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Figure 1

Model for how bintrafusp alfa may alter effector and suppressive elements in the tumor microenvironment to influence the response to immunotherapy.

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Model for how bintrafusp alfa may alter effector and suppressive element...
Tumors with low antitumor reactivity are characterized by interferon (IFN) production, decreased PD-L1 expression, a paucity of TILs or tissue resident memory T cells, an immunosuppressive (M2) monocytic phenotype, and a high number of Tregs and PD-L1-expressing cells in close proximity to CD8+ T cells. Tumors with high antitumor reactivity, which can be susceptible to ICI, are characterized by (a) cytokine and growth factor signals that can drive dendritic cell recruitment and maturation, (b) a pro-inflammatory monocytic (M1) phenotype, (c) robust antigen-specific CD8+ T cell and Trm infiltration, (d) chemokine binding that recruits activated effector T cells from the lymph nodes, (e) upregulation of PD-L1, and (f) few, if any, Tregs or PD-L1-expressing cells in close proximity to CD8+ T cells. Redman et al. (8) showed that the PD-L1- and TGF-β-blocking agent bintrafusp alfa induced a systemic immune response characterized by expanded activated, antigen specific T cells. Bintrafusp alfa may also act via CXCR3 on CD8+ T cells to permit trafficking to the tumor.