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alterations in these pathways had both decreased CD8 T cell infiltration and worse survival outcomes [25,26] ,
indicating inhibition of antigen presentation may play a key role in head and neck tumor immune escape.

Once primed, APCs interact with and activate CTLs. Activation of CTLs occurs through contact between
the T cell receptors and MHC class I bound to TA. This process requires a co-stimulatory signal between
CD80 (present on the surface of the APC) and CD28 (a surface receptor on the CTL). Conversely, CD80
may instead bind CTL associated antigen 4 (CTLA-4) leading to CTL inhibition [11,27,28] . While in normal
physiologic conditions, the CTLA-4 immune checkpoint prevents an exaggerated immune response, in the
setting of malignancies, it is thought to be a major mechanism of immune escape [27,28] .

Immune cell trafficking and infiltration
After priming and activation, CTLs infiltrate the tumor where they identify malignant cells displaying the
specific TAs. In order for successful immune cell trafficking to occur, there must be appropriate cytokine
signaling as well as an optimized physical environment. Physical blockade of immune cell infiltration has
been suggested to play a role in immune escape and is thought to be mediated through elevated vascular
endothelial growth factor (VEGF) signaling. This results in increased angiogenesis and increased oncotic
[29]
pressure within the tumor creating a physical barrier to infiltration . In vivo studies evaluating anti-
angiogenic tyrosine kinase inhibitors have shown an increase in tumor infiltrating lymphocytes correlating
with reduced angiogenesis [30,31] . Tumors may also promote an immune deplete environment through
recruitment of suppressive and regulatory immune cells. This is achieved through direct secretion of
suppressive cytokines such as tumor growth factor beta (TGF-β), or through secretion of CCL, CXCL, or
VEGF which recruit myeloid derived suppressor cells (MDSC) [32-34] . MDSCs are able to directly induce
[35]
[36]
T cell tolerance through arginase, nitric oxide synthase and indoleamine 2,3-dioxygenase (IDO)
dependent mechanisms [32,37,38] . In HNSCC, increased tumor lymphocyte infiltration is linked to improved
prognosis [39-41] , while elevated levels of MDSCs have been linked worse prognosis [38,42] .
PD-1/PD-L1 axis inhibition
Once in the tumor, CTLs induce tumor cell death. However, tumor cells may inhibit cell killing via co-
stimulatory signals through the PD-1/PD-L1 axis. PD-1 is a member of the CD28 superfamily and is
expressed on dendritic cells, regulatory T cells (Treg), CD8 and CD4 T cells, MDSCs, and natural killer
[43]
cells (NK) . PD-L1 is expressed on APCs and causes T cell anergy and apoptosis upon binding with
PD-1 receptors, thereby serving as a check to prevent an overactive immune response [44,45] . However,
upregulation of PD-L1 or additional PD-1 ligands such as PD-L2 can also be seen on tumor cells and
[46]
acts as a mechanism of immune escape in various malignancies . The interaction between PD-L1 and
PD-1 is complex and has been previously explored in multiple reviews [47,48] . In HNSCC, PD-1/PDL-1
expression has been reported in 46%-100% of tumors and with higher expression in HPV-positive tumors
compared to HPV negative tumors [46,49-51] . Multiple currently approved therapeutics have been developed
to target the PD-1/PD-L1 axis, including Pembrolizumab and Nivolumab as well as additional therapeutics
that are currently undergoing clinical investigation such as Atezolizumab, and Durvalumab among
others [Figure 1]. Both Pembrolizumab and Nivolumab inhibit PD-1, while the latter 2 (Atezolizumab
and Durvalumab) target PD-L1. As PD-1 can be activated by additional ligands such as PD-L2 there is a
theoretical advantage to targeting PD-1 over PD-L1, however anti-PD-1 and anti-PD-L1 therapies have
demonstrated similar response rates and toxicity profiles in clinical trials as discussed below.

IMMUNOMODULATORY MECHANISMS OF TRADITION THERAPIES
Prior to review of current immunotherapeutics, it is prudent to discuss the immunomodulatory role of
traditional therapies. Both platinum based chemotherapy and radiation have been shown to alter the
tumor immune microenvironment. In vivo studies revealed that cisplatin treatment increases expression
[52]
of MHC class I and antigen presentation machinery in patient derived HNSCC cell lines . While these