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Master Thesis

Analyse de l’expression de PD-L1 par les carcinomes non à petites cellules pulmonaires et de CD103 par le microenvironnement tumoral : analyse clinique, histologique et immunohistochimique d’une cohorte de 70 patients traités par nivolumab et de 74 patients opérés d’un adénocarcinome pulmonaire

Abstract : First part. Aims: PD-L1 expression is the only biomarker currently used to predict efficiency of immune checkpoint inhibitors but it is an imperfect and variable biomarker. Nivolumab demonstrated improved survival over docetaxel in patients who experience failure with platinum doublet therapy independently of PD-L1 expression. In the present study, we evaluated overall survival and response rate of patients who had advanced NSCLC treated with nivolumab in second line according to PD-L1 expression. Methods: PD-L1 expression was evaluated retrospectively in 70 pretreatment tumor-biopsy specimens, independently of histological type, with the SP142 scoring on tumor cells and immun cells (TC0 : PD-L1<1% ; TC1 1-4% ; TC2 : 5-49% ; TC3 ≥50% et IC0 : PD-L1<1% ; IC1 1-4% ; IC2 : 5-10% ; IC3 ≥10%). The antibody used is a monoclonal antibody anti-PD-L1 (E1L3N, Cell Signaling) with a Leica Bond III automat. Tumor microenvironment was also evaluated with antibodies anti-CD8 and anti-CD103. Results: PD-L1 was tested over 72,8% of patients with 41,4% TC0, 2,9% TC1, 17,1% TC2 et 11,4% TC3. Overall survival was not significantly different according to PD-L1 expression by tumor cells (p=0,203) or immun cells (p=0,662). The response rate was 88% with PD-L1 expression ≥50%, 48% with PD-L1= 1-49% and 36% with PD-L1<1% but they were not significantly different (p=0,069). Intratumoral immun cells CD103+ or CD8+ did not demonstrate improved survival or better response but CD103 was associated with PD-L1 expression. Conclusion: PD-L1 expression by tumor cells or immune cells don’t seem to influence overall survival or therapeutic response with nivolumab. SECOND PART AIMS PD-L1 was an imperfect biomarker. Therefore, biomarkers such as tumor mutation burden or tumor microenvironment were developed. In this second part, we evaluated histopronostic factors associated with PD-L1 expression and the value of intratumoral immun cells CD103+ or CD8+ as biomarkers. Methods: PD-L1, CD8 and CD103 expressions were evaluated retrospectively in 74 pretreatment tumor-chirurgical specimens of pulmonary adenocarcinoma. Histological type and realization of molecular analysis were selection criteria. We used the same scoring as the first part. Results: solid adenocarcinoma, tumor necrosis, mitosis and immune cells CD8+ were histopronostic factors associated with PD-L1 expression by tumor cells (p<0,001). A driver mutation seems to decrease PD-L1 expression. CD103+ immun cells were associated with PD-L1 expression by tumor cells (p=0,001) and immun cells (p=0,003) with a progressive increase. There isn’t CD103 heterogeneity expression and CD103 was easier to use in practice. Free-progression survival seems to be longer when PD-L1 expression decreases (p=0,0189). There is not significant difference according to CD103 or CD8 expression of intratumoral immun cells. Conclusion : intratumoral immun cells CD103+ is a promising biomarker. A larger study is needed to confirm this hypothesis and to find specific cut-offs.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-01806274
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Lisa Maloberti. Analyse de l’expression de PD-L1 par les carcinomes non à petites cellules pulmonaires et de CD103 par le microenvironnement tumoral : analyse clinique, histologique et immunohistochimique d’une cohorte de 70 patients traités par nivolumab et de 74 patients opérés d’un adénocarcinome pulmonaire. Médecine humaine et pathologie. 2018. ⟨dumas-01806274⟩

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