Aim: In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC). Methods: The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context. Results: High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity (P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors. Conclusions: In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations.

Retrospective immunophenotypical evaluation of MET, PD-1/PD-L1, and mTOR pathways in primary tumors and pulmonary metastases of renal cell carcinoma: the RIVELATOR study addresses the issue of biomarkers heterogeneity / Bersanelli, Melissa; Gnetti, Letizia; Pilato, Francesco Paolo; Varotti, Elena; Quaini, Federico; Campanini, Nicoletta; Rapacchi, Elena; Camisa, Roberta; Carbognani, Paolo; Silini, Enrico Maria; Rusca, Michele; Leonardi, Francesco; Maestroni, Umberto; Rizzo, Mimma; Brunelli, Matteo; Buti, Sebastiano; Ampollini, Luca. - In: EXPLORATION OF TARGETED ANTI-TUMOR THERAPY. - ISSN 2692-3114. - (2023), pp. 743-756. [10.37349/etat.2023.00165]

Retrospective immunophenotypical evaluation of MET, PD-1/PD-L1, and mTOR pathways in primary tumors and pulmonary metastases of renal cell carcinoma: the RIVELATOR study addresses the issue of biomarkers heterogeneity

Bersanelli, Melissa;Gnetti, Letizia
Investigation
;
Pilato, Francesco Paolo
Investigation
;
Varotti, Elena
Investigation
;
Quaini, Federico
Conceptualization
;
Campanini, Nicoletta
Investigation
;
Carbognani, Paolo
Membro del Collaboration Group
;
Silini, Enrico Maria
Investigation
;
Rusca, Michele
Membro del Collaboration Group
;
Leonardi, Francesco
Membro del Collaboration Group
;
Maestroni, Umberto
Membro del Collaboration Group
;
Buti, Sebastiano
Conceptualization
;
Ampollini, Luca
Supervision
2023-01-01

Abstract

Aim: In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC). Methods: The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context. Results: High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity (P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors. Conclusions: In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations.
2023
Retrospective immunophenotypical evaluation of MET, PD-1/PD-L1, and mTOR pathways in primary tumors and pulmonary metastases of renal cell carcinoma: the RIVELATOR study addresses the issue of biomarkers heterogeneity / Bersanelli, Melissa; Gnetti, Letizia; Pilato, Francesco Paolo; Varotti, Elena; Quaini, Federico; Campanini, Nicoletta; Rapacchi, Elena; Camisa, Roberta; Carbognani, Paolo; Silini, Enrico Maria; Rusca, Michele; Leonardi, Francesco; Maestroni, Umberto; Rizzo, Mimma; Brunelli, Matteo; Buti, Sebastiano; Ampollini, Luca. - In: EXPLORATION OF TARGETED ANTI-TUMOR THERAPY. - ISSN 2692-3114. - (2023), pp. 743-756. [10.37349/etat.2023.00165]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2959172
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