Comunicación

DYNAMICS OF PERIPHERAL BLOOD IMMUNE PROFILING ASSOCIATED WITH TUMOUR PROGRESSION IN METASTATIC CASTRATION RESISTANT PROSTATE CANCER (MCRPC).

Autores:

Enrique Pérez Navarro1, V. Conteduca2, Aránzazu González-del-Alba3, Begona Mellado4, Paolo Cremaschi5, Ovidio Fernandez-Calvo6, María José Méndez-Vidal7, Miguel Angel Climent8, Ignacio Duran9, Enrique Gallardo10, Angel Rodriguez Sanchez11, Sergio Vázquez-Estévez12, Albert Font13, MARIA PIEDAD FERNÁNDEZ PÉREZ1, ALBERTO MARTINEZ CARRASCO14, Maria José López Andreo15, Gerhardt Attard5, Daniel Castellano16, Enrique Grande17, Ugo de Giorgi2, Juan Antonio Botia Blaya18, Jose Tomás Palma Mendez19, Enrique Gonzalez Billalabeitia1

Afiliaciones:

(1) HEMATOLOGÍA Y ONCOLOGÍA MÉDICA CLÍNICO-EXPERIMENTAL, IMIB-Arrixaca, España
(2) Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Italia
(3) Department of Medical Oncology, España (Islas Baleares)
(4) Department of Medical Oncology. IDIBAPS. Hospital Clinic,, España (Cataluña)
(5) University College London Cancer Institute, Reino Unido
(6) Department of Medical Oncology. Complejo Hospitalario Universitario Ourense, España (Galicia)
(7) Department of Medical Oncology. Hospital Universitario Reina Sofía (HURS), Maimonides Institute for biomedical research of Córdoba (IMIBIC)., España (Andalucía)
(8) Servicio de Oncología Médica. Instituto Valenciano de Oncología, España (Comunidad Valenciana)
(9) Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, España (Andalucía)
(10) Department of Medical Oncology. Servicio de Oncología Médica. Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT, España (Cataluña)
(11) Department of Medical Oncology. Hospital Universitario de León, España (Castilla y León)
(12) Department of Medical Oncology. H. Universitario Lucus Augusti, España (Galicia)
(13) Department of Medical Oncology. Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (BARGO),, España (Cataluña)
(14) PLATAFORMA DE BIOBANCO, IMIB-Arrixaca, España
(15) BIOMEMBRANAS Y SEÑALIZACIÓN CELULAR, IMIB-Arrixaca, España
(16) Medical Oncology Department. Hospital 12 de Octubre., España (Comunidad de Madrid)
(17) 18 Enrique Grande MD Anderson Cancer Center Madrid, España (Comunidad de Madrid)
(18) Department of Communications and Information Engineering UMU, España (Región de Murcia)
(19) Department of Communications and Information Engineering UMU,, España (Región de Murcia)

Comunicación:

Antecedentes:

At present we do not have any validated tool that allows us to personalize treatment in first-line Metastatic Castration-Resistant Prostate Cancer (mCRPC), basing our decisions on clinical criteria and the safety profile of the treatments. Resistance to enzalutamide and androgen signaling inhibitors (ARSI) is invariable and a major health concern. Disseminated prostate cancer interacts very significantly with the hematopoietic and immune system, generating changes that in advanced stages of the disease are evident in peripheral blood in a simple hemogram. The study of the tumor microenvironment can provide us with new useful tools for clinical decision and allow us to identify therapeutic vulnerabilities present in the tumor microenvironment. We hypothesized that tumor progression is associated with host-derived immune-evasion mechanisms that could be detected by changes in peripheral blood cells.

Métodos:

We analyzed dynamic changes in peripheral blood gene expression in mCRPC patients treated with enzalutamide in the prospective multi-center PREMIERE trial (NCT02288936). An independent single-center prospective cohort was used for validation. Whole-blood RNA was collected using PAXgene RNA tubes and analyzed using Affymetryx HTA 2.0 microarrays. Bioconductor packages and R software were used for gene expression analyses. A machine learning method, CIBERSORT X, was used for blood–cell type deconvolution including 22 human immune subsets.

Resultados:

We analyzed 226 samples (basal (B)/progression (P)): 94/63 training; 54/15 validation. In the training set, we observed 629 genes differentially expressed at P compared to B. Pair-wise differential immune-cell profiling showed that tumor P was associated with expansion of monocytes (p < 0.002) and contraction of T-cell lymphocytes (p<0.005). We then analyzed the prognostic value for monocytes and T cell lymphocytes in B samples from the training cohort, and observed a worse survival outcome for patients with high monocytes (Q1) compared with normal values (Q2-4) with median overall survival of 30.8 vs 38.3 months (HR=2.30, 95%CI: 1.30-4.18; p<0.005). Association was also observed between low T-cell lymphocytes (Q4) compared with normal values (Q1-Q3) in B with median overall survival of 28.3 vs 38.1 months (HR=2.0, 95%CI:1.13-3.68; p<0.018). We then confirmed a numerical increase in monocytes and decrease in T-cell lymphocytes at P in the validation cohort and validated both conditions in B with worse survival for high monocytes (HR = 2.2, 95%CI: 1.06-4.23; p< 0.03) and low T-cell lymphocytes (HR = 3.9, 95%CI: 1.95-7.93; <0.001).

Conclusiones:

Prostate cancer progression is associated with changes in peripheral blood that compromise activation of immune-regulatory components, including the expansion of monocytes and the reduction of T-cell lymphocytes . These findings could offer biomarker and therapeutic opportunities to reverse resistance to enzalutamide.


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