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

Abstract

Purpose: Adenoid cystic carcinoma (ACC) is a heterogeneous Results: RNA deconvolution revealed that most ACCs are immumalignancy, and no effective systemic therapy exists for metastatic nologically “cold,” with approximately 30% being “hot.” ACC-I disease. We previously described two prognostic ACC molecular tumors with a poor prognosis harbored a higher density of immune subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-cells; however, spatial analysis by IMC revealed that ACC-I immune II. In this study, we explored the ACC tumor microenvironment cells were significantly restricted to the stroma, characterizing an (TME) using RNA-sequencing and spatial biology to identify immune-excluded TME. ACC-I tumors overexpressed the immune potential therapeutic targets. checkpoint B7-H4, and the degree of immune exclusion was directly Experimental Design: Tumor samples from 62 ACC patients correlated with B7-H4 expression levels, an independent predictor of with available RNA-sequencing data that had been collected as poor survival. Two ACC-I/B7-H4-high PDXs obtained 90% com-part of previous studies were stained with a panel of 28 validated plete responses to a single dose of AZD8205, but none were observed metal-tagged antibodies. Imaging mass cytometry (IMC) was with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX. performed using the Fluidigm Helios CyTOF instrument and Conclusions: Spatial analysis revealed that ACC subtypes have analyzed with Visiopharm software. The B7-H4 antibody–drug distinct TMEs, with enrichment of ACC-I immune cells that are conjugate AZD8205 was tested in ACC patient-derived xenorestricted to the stroma. B7-H4 is highly expressed in poor-grafts (PDX). prognosis ACC-I subtype and is a potential therapeutic target.