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Stangl, S. ; Tontcheva, N.* ; Sievert, W. ; Shevtsov, M. ; Niu, M.* ; Schmid, T.E. ; Pigorsch, S.U. ; Combs, S.E. ; Haller, B.* ; Balermpas, P.* ; Rödel, F.* ; Rödel, C.* ; Fokas, E.* ; Krause, M.* ; Linge, A.* ; Lohaus, F.* ; Baumann, M.* ; Tinhofer, I.* ; Budach, V.* ; Stuschke, M.* ; Grosu, A.-L.* ; Abdollahi, A.* ; Debus, J.* ; Belka, C.* ; Maihöfer, C.* ; Mönnich, D.* ; Zips, D.* ; Multhoff, G.

Heat shock protein 70 and tumor-infiltrating NK cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

Int. J. Cancer 142, 1911-1925 (2018)

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Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre-activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor-infiltrating CD56(+) NK cells in formalin-fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N=145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin-based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3-4) showed significantly decreased overall survival (OS; p = 0.008), local progression-free survival (LPFS; p = 0.034) and distant metastases-free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0-2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16- (p = 0.001), p53- (p = 0.0003) and HPV16 DNA-negative (p = 0.001) tumors. The absence or low numbers of tumor-infiltrating CD56(+) NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor-infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor-infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers. What's new? It's difficult to predict how a patient with squamous-cell carcinoma of the head and neck (SCCHN) will respond to treatment, because every tumor is different. In this study, the authors identified two pre-treatment measures that were associated with poor prognosis following surgery and RCT: high levels of staining for a protein called Hsp70 in tumor cells, and low numbers of tumor-infiltrating NK lymphocytes. These measures may thus serve as useful prognostic biomarkers for predicting the response of SCCHN to therapy.

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