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factors include tobacco, alcohol, and more recently human papillomavirus (HPV). High risk strains of HPV
[2,3]
(HPV 16, 18) now are responsible for 70%-80% of oropharyngeal squamous cell carcinoma .

Treatment of HNSCC varies by tumor site and stage, however the mainstays of treatment include surgery,
radiation, and cytotoxic chemotherapy. Despite advancements in surgical and radiation techniques,
[4,5]
treatment failures occur in up to 50% of patients with HNSCC . In the unresectable recurrent or
metastatic (R/M) setting, chemotherapy has previously been the main therapeutic option, with dismal
[6]
outcomes and median survival times ranging from 6-10 months . Immunotherapy, particularly checkpoint
[7,8]
inhibitors, have shown promising results in R/M HNSCC . In June of 2019, the United States Food
and Drug Administration approved pembrolizumab as a 1st line treatment for patients based on PD-L1
[9]
expression in the tumor immune microenvironment . Despite these recent reports, overall response rates
remain low with underwhelming improvements in long term survival. Hence there continues to be a need
for novel therapeutic options.

Head and neck tumors display various derangements in anti-tumor immunity and detailed understanding
of these changes has led to development of currently approved immunotherapies. Here, we discuss
alterations in the tumor immune microenvironment, review the mechanism of current treatments and
focus on approaches for development of novel immunologic therapies.

DERANGEMENT OF HEAD AND NECK TUMOR IMMUNE MICROENVIRONMENT
Tumor immunity cycle
Anti-tumor immunity requires a complex set of interactions between the tumor and host immune system.
This process has been termed the cancer immunity cycle [10,11] . Initial tumor cell lysis results in release of
tumor specific antigens (TAs) and priming of antigen presenting cells (APCs). APCs then interact with host
immune cells resulting in activation and trafficking of cytoxic T cells (CTLs) into the tumor. Once in the
tumor, CTLs identify malignant cells displaying the specified tumor antigen and target them for cell death.
Tumor antigens also referred to as neoantigens have become an area of intense research. These can be
derived from either driver or passenger mutations and generation of TAs is thought to be closely linked to
mutational burden, with a higher mutational load correlating to increased TAs [12,13] . HNSCC has been found
to have 1 of highest mutational burdens of all malignancies, likely due to their relationship with carcinogen
exposure (i.e., tobacco smoke) which results in significant mutagenesis [13,14] . As sequencing techniques
have advanced, more sophisticated modeling has allowed for identification of specific mutational profiles
[15]
including smoking and APOBEC signatures as well as prediction of neoantigen load . Detailed review of
neoantigen prediction modeling has previously been published and is outside the scope of this review [16-19] .
Finally, with targeted tumor cell death by CTLs there is further release of tumor antigens resulting in
perpetuation of the cycle. Head and neck tumors have evolved multiple mechanisms of immune escape
which will be reviewed below in context of the cancer-immunity cycle.

Inhibition of antigen processing and presentation and immune cell activation
While HNSCC is thought to be highly antigenic, further steps are required for activation of a TA-specific
adaptive immune response. After being released from tumor cells, TAs are degraded, processed, and
presented by professional APCs including dendritic cells. Normal processes allow for extracellular protein
presentation through major histocompatibility complex (MHC) class II and CD4 interaction, however, for TA
[20]
to activate a CD8 response, cross presentation occurs, requiring an additional set of processing machinery .
Large scale sequencing studies as well as analysis of TCGA data have revealed that up to 20% of HNSCCs
contain alterations in antigen processing machinery (APM) or downregulation of MHC class I [20,21] . In HPV
positive tumors, the latter is thought to be mediated through viral oncoproteins, E5 and E7, which have been
shown to downregulate both MHC class I and class II [22-24] . Additional studies show that patients with