Spatial immune profiling complements genomic sequencing in biliary tract cancer: hypothesis-generating use cases

<h3>Background</h3> Personalized therapy approaches targeting homologous recombination deficiency (HRD) in biliary tract cancer (BTC) remain poorly explored with limited clinical data available. Beyond BRCA1/2, the therapeutic implications of BRCA1-associated protein 1 (BAP1) alterations are unclear. <h3>Materials and methods</h3> We describe three patients with BTC and HRD-related mutations as hypothesis-generating use cases. We illustrate how integration of multiplexed imaging mass cytometry-based spatial immune profiling with genomic sequencing may help generate testable biological hypotheses beyond genomics alone. <h3>Results</h3> A patient with germline <i>BRCA2</i>-mutated BTC together with a positive HRD score was sensitive to platinum-based therapy and poly (ADP-ribose) polymerase inhibition. In contrast, a patient with loss of <i>BAP1</i> was linked to a CD8+ T-cell enriched tumor microenvironment, classified as spatially immune enriched and responded long-term to subsequent immune checkpoint inhibition and tyrosine kinase inhibition therapy. <h3>Conclusion</h3> These observations provide a rationale for integrated genomic and spatial immune profiling in BTC, which will require further prospective validation.