Background: Immune checkpoint inhibitors (ICIs) have particular, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies depending on ICI class, administered dose and treatment schedule. The aim of this study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods: A prospective, multicenter study evaluating the immune profile (IP) of 79 patients with advanced cancer and treated with anti-programmed cell death protein 1 (anti-PD-1) drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. Indoleamine 2, 3-dioxygenase (IDO) activity was measured through a modified liquid chromatography-tandem mass spectrometry using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (35%). Positive and statistically significant correlations between the cumulative toxicity and IP10 and IL8, sLAG3, sPD-L2, sHVEM, sCD137, sCD27 and sICAM-1 serum concentration were found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern, characterized by disruption of most of the paired connections between cytokines, chemokines and connections of sCD137, sCD27 and sCD28, while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 statistically significant interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients who experienced toxicity. Conclusions: A particular, common pattern of immune dysregulation was defined in patients developing irAEs. This immune serological profile, if confirmed in a larger patient population, could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.

Immune-related toxicity and soluble profile in patients affected by solid tumors: a network approach / Botticelli, Andrea; Cirillo, Alessio; Pomati, Giulia; Cortesi, Enrico; Rossi, Ernesto; Schinzari, Giovanni; Tortora, Giampaolo; Tomao, Silverio; Fiscon, Giulia; Farina, Lorenzo; Scagnoli, Simone; Pisegna, Simona; Ciurluini, Fabio; Chiavassa, Antonella; Amirhassankhani, Sasan; Ceccarelli, Fulvia; Conti, Fabrizio; Di Filippo, Alessandra; Zizzari, Ilaria Grazia; Napoletano, Chiara; Rughetti, Aurelia; Nuti, Marianna; Mezi, Silvia; Marchetti, Paolo. - In: CANCER IMMUNOLOGY, IMMUNOTHERAPY. - ISSN 1432-0851. - (2023). [10.1007/s00262-023-03384-9]

Immune-related toxicity and soluble profile in patients affected by solid tumors: a network approach

Botticelli, Andrea
Co-primo
;
Cirillo, Alessio
Co-primo
;
Pomati, Giulia;Cortesi, Enrico;Tomao, Silverio;Fiscon, Giulia;Farina, Lorenzo;Scagnoli, Simone;Pisegna, Simona;Ciurluini, Fabio;Chiavassa, Antonella;Ceccarelli, Fulvia;Conti, Fabrizio;Di Filippo, Alessandra;Zizzari, Ilaria Grazia;Napoletano, Chiara;Rughetti, Aurelia;Nuti, Marianna;Mezi, Silvia
Co-primo
;
Marchetti, Paolo
Co-primo
2023

Abstract

Background: Immune checkpoint inhibitors (ICIs) have particular, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies depending on ICI class, administered dose and treatment schedule. The aim of this study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods: A prospective, multicenter study evaluating the immune profile (IP) of 79 patients with advanced cancer and treated with anti-programmed cell death protein 1 (anti-PD-1) drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. Indoleamine 2, 3-dioxygenase (IDO) activity was measured through a modified liquid chromatography-tandem mass spectrometry using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (35%). Positive and statistically significant correlations between the cumulative toxicity and IP10 and IL8, sLAG3, sPD-L2, sHVEM, sCD137, sCD27 and sICAM-1 serum concentration were found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern, characterized by disruption of most of the paired connections between cytokines, chemokines and connections of sCD137, sCD27 and sCD28, while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 statistically significant interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients who experienced toxicity. Conclusions: A particular, common pattern of immune dysregulation was defined in patients developing irAEs. This immune serological profile, if confirmed in a larger patient population, could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.
2023
immunotherapy; network; solid tumors; soluble profile; toxicity
01 Pubblicazione su rivista::01a Articolo in rivista
Immune-related toxicity and soluble profile in patients affected by solid tumors: a network approach / Botticelli, Andrea; Cirillo, Alessio; Pomati, Giulia; Cortesi, Enrico; Rossi, Ernesto; Schinzari, Giovanni; Tortora, Giampaolo; Tomao, Silverio; Fiscon, Giulia; Farina, Lorenzo; Scagnoli, Simone; Pisegna, Simona; Ciurluini, Fabio; Chiavassa, Antonella; Amirhassankhani, Sasan; Ceccarelli, Fulvia; Conti, Fabrizio; Di Filippo, Alessandra; Zizzari, Ilaria Grazia; Napoletano, Chiara; Rughetti, Aurelia; Nuti, Marianna; Mezi, Silvia; Marchetti, Paolo. - In: CANCER IMMUNOLOGY, IMMUNOTHERAPY. - ISSN 1432-0851. - (2023). [10.1007/s00262-023-03384-9]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1674348
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