Studio del valore prognostico di CD38 nei tumori polmonari non a piccole cellule (NSCLC) con il supporto della Digital Pathology: possibile ruolo di CD38 come target di terapie mirate

BACKGROUND In NSCLC, PD-L1 Tumor Proportion Score (TPS)>1% allows Immune checkpoint inhibitor (ICI) therapies, significantly improving patients’prognosis. However, several patients develop resistance. The membrane molecule CD38, a multifunctional enzyme, has been found upregulated in NSCLC. Particularly in murine models of lung cancer, CD38 increases in tumor cells in association with resistance to PD-1/PD-L1 blockade and is found to inhibit the cytotoxic activity of CD8+ T cells in vitro. Moreover, CD38 is increased in exhausted CD8+ Tcells6 and immunosuppressive Tregs in the tumor microenvironment (TME). OBJECTIVES The aim of this study was to evaluate CD38 expression in lung sections, prior ICI therapy, distinguishing CD38 positivity in tumor and TME by digital pathology. CD38 expression was evaluated in relationship with PD-L1 and related to the ICI therapeutic response or resistance. MATERIALS AND METHODS We retrospectively collected a series of 34 NSCLC cases from 2021 to 2023. The histological diagnoses of NSCLC were performed at the Units of Anatomy and Pathologic Histology of the AOUP "P. Giaccone", University of Palermo and Umberto I° Hospital of Enna. As exclusion criteria we considered:(i) inadequate samples;(ii) history of other malignancy within 10 years prior to diagnosis of NSCLC;(iii) previously administrated ICI therapy. Sections of 5 μm were employed for immunohistochemical staining of CD38 and PD-L1 (DAKO), and slide were scanned at 40x as TIF file using the Aperio ScanScope CS (Leica Biosystems). The software QuPath v0.5.1 was employed for digital analysis, annotating tumor and stroma.RESULTS Digital and semiquantitative analysis of CD38 showed high correlation in PD-L1 positive cases (p<0.0001).The CD38% resulted significantly increased in progressing cases respect to responders, for both tumoral and stromal components (p<0.05). More importantly, ROC curve indicated that CD38% discriminated progression from response at thresholds of 17.71% (in TME), with sensitivity of 75% and specificity of 100%, and of 3 % (in tumor), with sensitivity of 100% and specificity of 70%.CONCLUSIONS The present data could be promising to identify non responders to ICI therapy in NSCLC, suggesting novel therapeutic strategies.