Functionally Active Lymphoid Aggregates Correlate with Improved Prognosis in Brain Metastases

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Abstract
B cells and their cellular neighborhoods, i.e., lymphoid aggregates (LA) and tertiary lymphoid structures (TLS), have not been extensively studied in melanoma brain metastases (BM) or lung adenocarcinoma BM, despite their prognostic value and role in immunotherapeutic responses. In this study, we evaluated the prognostic benefit and heterogeneity of B-cell infiltration and LA formation in more than 200 patients with melanoma BM or lung adenocarcinoma BM. We found that LAs were associated with increased intratumoral CD8+ T cells in melanoma BM compared with lung adenocarcinoma BM. Moreover, the presence of LAs was associated with an increased survival benefit in patients with melanoma BM but not in those with lung adenocarcinoma BM. Despite lacking canonical TLS hallmarks, LAs in BM contained proliferating B and T cells with the potential for effector function. Our work has solidified the need for the mechanistic investigation of intracranial B cells and the immune neighborhoods in which they reside. Significance: Among tumor metastases, patients with BM are considered to have the greatest mortality and very limited therapeutic options. This study uncovers immunologically active LAs as potential orchestrators of CD8+ T cell–mediated antitumor immunity in melanoma BM, emphasizing their potential as a therapeutic target within the unique tumor microenvironment of the brain.
Funding Information
  • Department of Defense Education Activity (W81XWH-22-1-0694/ME210201)
  • National Institute of General Medical Sciences (T32GM144300)
  • Hillman Cancer Center, Medical Center, University of Pittsburgh (P30CA047904)
  • NSABP Foundation
  • National Institutes of Health (S10OD028483)
  • University of Texas MD Anderson Cancer Center