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Gauduchon et al. J Cancer Metastasis Treat 2019;5:72 I http://dx.doi.org/10.20517/2394-4722.2019.023 Page 7 of 9

immunological toxicity. These patients had higher response rates (30.6% vs. 12.3%), better progression-
free survival (6.9 months vs. 2.1 months) and improved overall survival (12.5 months vs. 6.8 months). This
analysis may of course be biased since patients who benefit from immunotherapy pursue it longer and are
[21]
therefore more likely to develop immunological toxicity .

PREDICTIVE FACTOR OF EFFICACY OF IMMUNOTHERAPY
One of the major challenges of immunotherapy is to select patients responding to immunotherapies with
predictive biomarkers of effectiveness. Currently, the only one used is the expression of PDL1 but it is very
imperfect, especially with excellent results in PDL1 negative patients.

The expression of PD-L2 and the signature IFNγ have been explored, but do not seem particularly
convincing.

HNSCC have been classified into 6 groups: immunoreactive, inflammatory, Human Papilloma Virus
[22]
(HPV)-like, classical, hypoxemic and mesenchymal . The inflammatory and immunoreactive profiles are
probably more sensitive to immunotherapies because they are strongly infiltrated by cells of the immune
system. The important tumoral infiltration by the CD8 lymphocytes could characterize this inflammatory
type.

In a cohort of 34 patients with significan CD8+ lymphocyte infiltration and a high PD-1/TIM3 expression
ratio (regardless of HPV status and smoking status) showed an increase in overall survival (84 months vs.
13 months) with anti-PD-1 treatment, compared with non-inflammatory tumors .
[23]
The estimation of the mutational load (TMB) in the primary tumor, but also from the circulating DNA
[24]
could also become a predictive biomarker .

There is also evidence that HPV-positive tumors may be better able to respond to anti-PD1. There is indeed
a biological rationale for better efficacy of anti-PD1 in HPV + tumors since they show more immune
infiltrates and more markers of activated T cells. A retrospective analysis of 54 patients treated after
platinum failure with pembrolizumab (32 patients) or nivolumab (22) overall survival was significantly
better for HPV positive patients: 17 months vs. 4.5 months. Similarly, the duration of anti-PD1 treatment
[25]
was significantly increased in positive HPV: 7 months vs. 3 months .
Much simpler, a study presented at ASCO 2018 has recently been shown to have a high lymphocyte
[26]
neutrophil count associated with tumor inflammation and poor prognosis . The 114 patients were treated
with anti-PD1 classified in 4 quartiles according to this ratio. Patients with the lowest ratio had an overall
survival well above 12.5 months compared to those with the highest ratio (4.1 months, P <0.0001). In this
cohort, PD-L1 expression did not discriminate patients. Thus, a very simple and clinical marker proves to
be a powerful prognostic factor for the efficacy of immunotherapies.

CONCLUSION
Squamous cell carcinoma of the head and neck has not been spared by the revolution of immunotherapy.
Indeed, the CPIs are now an integral part of the therapeutic arsenal and new indications are emerging
either as monotherapy or in combination. In addition, many other classes of molecules are currently under
development. The selection of patients who will benefit most from immunotherapy with new biomarkers
remains an important challenge in the use of these new therapies. The question of the optimal duration
and determination of the best combinations of these immunotherapy treatments remains unresolved. The
therapeutic management of HNSCC cancers will continue to be disrupted in the coming years.