Why responses to immune checkpoint inhibitors are heterogeneous in head and neck cancers: Contributions from tumor-intrinsic and host-intrinsic factors

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment including in head and neck squamous cell carcinomas (HNSCCs); however, only a fraction of HNSCC patients respond to ICI, whereas the majority fail to do so. The mechanisms underlying such variable responses remain incompletely understood. A better understanding of such mechanisms may broaden the spectrum of responding patients and enhance the rate of ICI response. HNSCCs exhibit a high level of genetic heterogeneity, manifested as mutations or amplifications of oncogenes (e.g., PIK3CA) and mutations of tumor suppressor genes (e.g., TP53). The immune tumor microenvironment (TME) of HNSCCs also varies significantly in composition and in relative abundance of distinct immune subsets such as CD8 tumor-infiltrating lymphocytes (TILs) or tumor-associated macrophages (TAMs), which represents a high degree of immunological heterogeneity. Here, we briefly discuss how heterogeneous ICI responses may be attributed to tumor-intrinsic factors, including genetic, transcriptional, and functional variations in tumor cells, and host-intrinsic factors, including cellular composition of the TME (e.g., CD8 TILs and TAMs), and host-intrinsic differences in the T cell receptor (TCR) repertoire of CD8 TILs. We also discuss the potential impact of these factors on designing strategies for personalized immunotherapy of HNSCCs.