Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors.

Autor:	Sousa LG; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., McGrail DJ; Lerner Research Institute, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, Ohio., Lazar Neto F; Instituto do Cancer do Estado de Sao Paulo, Sao Paulo University, Sao Paulo, Brazil., Li K; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Marques-Piubelli ML; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ferri-Borgogno S; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Dai H; Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Mitani Y; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Spardy Burr N; Adenoid Cystic Carcinoma Research Foundation, Needham, Massachusetts., Cooper ZA; Oncology R&D, AstraZeneca, Gaithersburg, Maryland., Kinneer K; Oncology R&D, AstraZeneca, Gaithersburg, Maryland., Cortez MA; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lin SY; Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bell D; Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California., El Naggar A; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Burks J; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ferrarotto R; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Aug 15; Vol. 29 (16), pp. 3162-3171.
DOI:	10.1158/1078-0432.CCR-23-0514
Abstrakt:	Purpose: Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets. Experimental Design: Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm software. The B7-H4 antibody-drug conjugate AZD8205 was tested in ACC patient-derived xenografts (PDX). Results: RNA deconvolution revealed that most ACCs are immunologically "cold," with approximately 30% being "hot." ACC-I tumors with a poor prognosis harbored a higher density of immune cells; however, spatial analysis by IMC revealed that ACC-I immune cells were significantly restricted to the stroma, characterizing an immune-excluded TME. ACC-I tumors overexpressed the immune checkpoint B7-H4, and the degree of immune exclusion was directly correlated with B7-H4 expression levels, an independent predictor of poor survival. Two ACC-I/B7-H4-high PDXs obtained 90% complete responses to a single dose of AZD8205, but none were observed with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX. Conclusions: Spatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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