Head and Neck Cancer Immunotherapy beyond the Checkpoint Blockade

Abstract

The success of immune checkpoint receptor blockade has brought exciting promises for the treatment of head and neck squamous cell carcinoma (HNSCC). While patients who respond to checkpoint inhibitors tend to develop a durable response, <15% of patients with HNSCC respond to immune checkpoint inhibitors, underscoring the critical need to alleviate cancer resistance to immunotherapy. Major advances have been made to elucidate the intrinsic and adaptive resistance mechanisms to immunotherapy. Central genomic events in HNSCC have been found to possess previously unknown roles in suppressing immune sensing. Such inhibitory function affects both the innate and adaptive arms of tumor-specific immunity. While checkpoint blockade effectively reinvigorates adaptive T-cell responses, additional targeting of the oncogenic inhibitors of innate immune sensing likely informs a novel and potent strategy for immune priming. This review discusses the recent advances on the identification of key HNSCC oncogenes that impair antitumor immunity and emerging immune-priming approaches that sensitize poorly immunogenic HNSCCs to checkpoint blockade. These approaches include but are not limited to cancer vaccine systems utilizing novel type I interferon agonists as immune adjuvants, radiation, DNA damage-inducing agents, and metabolic reprogramming. The goal of these multipronged approaches is to expand tumor-specific effector T-cells, break checkpoint receptor-mediated tolerance, and metabolically support sustained T-cell activation. The translation of therapeutics that reverses oncogenic inhibition of immune sensing requires thorough characterization of the HNSCC regulators of innate immune sensors, development of additional immunocompetent HNSCC mouse models, as well as engineering of more robust immune adjuvant delivery systems. Built on the success of checkpoint blockade, validation of novel immune-priming approaches holds key promises to expand the pool of responders to immunotherapy.

Keywords: cancer vaccines; glycolysis; head and neck cancer; immunotherapy; innate immunity; type I interferon.

Figure 1.

Genetic abnormalities in HNSCC contribute to poor tumor immunogenicity. Aberrant signaling resulting from genes controlling processes, ranging from self-renewal to metabolism, can lead to deficits in cancer immunogenicity. The transcription factor SOX2 has been recently implicated in negatively regulating IFN-I-mediated antitumor immune responses by promoting the autophagosome-mediated degradation of the endoplasmic reticulum–resident protein STING, leading to decreased immune infiltration. PIK3CA is commonly coamplified with SOX2 in HNSCC, leading to the activation of the mTOR pathway, which reduces CTL infiltration into the tumor microenvironment. CTL, cytotoxic T lymphocyte; HNSCC, head and neck cancer squamous cell carcinoma; IFN, interferon; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; TCR, T-cell receptor.

Figure 2.

Strategies to sensitize cold HNSCC to ICR blockade. A multipronged approach is needed to most effectively prime the tumor microenvironment for ICR blockade. The goal of immune priming is to release frequent oncogenic inhibitors of the innate and adaptive immune signaling, to expand the pool of tumor-specific CTLs, and to metabolically support the activation of antigen-presenting cells and effectors. Some immune-priming approaches have shown promises in HNSCC immunotherapy, including but not limited to cancer vaccines, radiotherapy, DNA damage–inducing chemotherapy, and metabolic reprograming agents. CTL, cytotoxic T lymphocyte; HNSCC, head and neck cancer squamous cell carcinoma; ICR, immune checkpoint receptor.