Combining Radiation and Immune Checkpoint Blockade in the Treatment of Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide. Current treatment options, even though potentially curative, have many limitations including a high rate of complications. Over the past few years immune checkpoint inhibitors (ICI) targeting cytotoxic lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have changed treatment paradigms in many malignancies and are currently under investigation in HNSCC as well. Despite improvements in treatment outcomes and the implementation of combined modality approaches long-term survival rates in patients with locally advanced HNSCC remain suboptimal. Accumulating evidence suggests that under certain conditions, radiation may be delivered in conjunction with ICI to augment efficacy. In this review, we will discuss the immune modulating mechanisms of ICI and radiation, how changing the dose, fractionation, and field of radiation may alter the tumor microenvironment (TME), and how these two treatment modalities may work in concert to generate durable treatment responses against HNSCC.

Keywords: PD-L1; PD1; abscopal effect; immune checkpoint inhibitors; immunotherapy; radiation therapy.

Figure 1

Radiation simultaneously induces immune suppression and immune activation in the TME. RT induces dsDNA damage both directly and indirectly by ROS formation. Activation (Right): RT triggers release of the cytokines IL-1β, TNF-α, and IL-6 which promote inflammation and inhibit tumor proliferation while IFN-β promotes DC recruitment. CRT expression by the irradiated tissue binds to CD91 on DCs which promotes phagocytosis. Increased antigen uptake by DCs and activation by HMGB1 binding to TLR4 leads to CTL cross priming in draining lymph nodes. Recognition of cognate antigen by the naïve CTL provides Signal 1 required for CTL maturation. Co-stimulation (signal 2) by CD80/86 on the DC with CD28 on the CTL leads to upregulation of the high-affinity IL-2 receptor, CD25, as well as IL-2 secretion by the CTL which promotes T cell proliferation and survival. Release of the chemokines CXCL9, CXCL10, and CXCL16 recruit activated CTLs to the TME which recognize their cognate antigen via MHC class I molecules on the tumor surface. This in turn initiates cytolysis via release of cytokines (IFN-γ, TNF-α), cytotoxic granules (Granzymes, perforins), and direct cell-cell interactions (Fas-Fas ligand). Suppression (Left): CSF-1 promotes recruitment of TAMs to the TME. Production of IL-10 and TGF-β by the TAM promotes Treg recruitment. Together, release of IDO enhances tryptophan consumption resulting in CTL starvation. PD-L1 expression by tumor, TAMs, and Tregs impairs cytotoxicity of activated CTL and promotes exhaustion. Expression of CD25 by Tregs competes with CTL uptake of IL-2 thus indirectly impairing CTL proliferation and survival. CTLA4 expressed by both Tregs and DCs competes with CD80/CD86 for CD28 co-stimulation (signal 2) thus preventing CTL activation and promoting anergy.