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Lo Re et al. J Cancer Metastasis Treat 2020;6:17 I http://dx.doi.org/10.20517/2394-4722.2020.11 Page 7 of 9

with consequent depletion of tryptophan determines immunosuppression through their blocking of the
[42]
maturation and induction of T cell apoptosis .

Considering the key immunosuppressive role played by these cells, with Tregs and MDSCs being the
[43]
most studied, and their negative relationship with tumor stage, prognosis, and resistance to treatment ,
preliminary experience with Cyc and FU, active on both types of suppressive cells, combined with IL-2 was
reported in heavily pre-treated solid tumors, with interesting results both from a clinical and laboratory
[44]
point of view .

Our patient with advanced cSCC showed for the first time how a chemo-immunotherapy regimen
including IL-2 was able to produce a fleeting response even on the primary and more-lasting tumor
response on the metastatic lesion. Furthermore, the blood count and immunophenotype showed an
initial increase in white blood cells, neutrophilic granulocytes and lymphocytes followed by their decrease
[Figure 4A] and a transient decrease in the Treg count during chemo-immunotherapy [Figure 4B],
respectively. In addition, a subsequent decrease in Tregs was observed during salvage chemotherapy
[Figure 4B]. This transient effect could be explained by the concomitant presence of lymphomas and
Treg stimulation by IL-2 with detrimental effect on the immune system with consequent unfavorable
response to chemo-immunotherapy. A more favorable outcome could be hypothesized in the presence of
adequate immunosurveillance especially in a high TMB tumor such as cSCC. A confirmation of the poor
efficacy of chemotherapy along with the combination of carboplatin and paclitaxel employed after chemo-
immunotherapy failure, despite the theoretical synergism and additive antitumor activity for increase of
[45]
carboplatin-DNA adduct formation , has been reported. Noteworthy is the ability of a fluoropyrimidine
(Cape) to reverse resistance to the previous carboplatin combination therapy through the upregulation of
thymidine phosphorylase activity by paclitaxel and subsequent Cape activation [22,46] , the decrease of Treg
count and tumor response.

In conclusion advanced spinocellular carcinoma of the skin remains a pathology with severe treatment
difficulties due to primary resistance, worsened by a state of immunosuppression resulting from organ
transplantation or other tumors. It is desirable to improve our knowledge of the resistance mechanisms
and to investigate prospectively innovative therapeutic strategies to improve the therapeutic index and the
control of the disease.

DECLARATIONS
Acknowledgments
We warmly thank Dr. Federica G. Ravizza for editing. Finally, we thank the doctors and nurses who
supported us in this study.

Authors’ contributions
Conceptualization: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A
Data curation: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Formal analysis: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Investigation: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Project administration: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A
Software: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Supervision: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Validation: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Visualization: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Writing - original draft: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Writing - review and editing: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S
Used in attributes: Lo Re G, Doretto P, Lo Re F, Matrone F, Ermacora A, Marus W, Pizzichetta MA, Sulfaro S