Shared B cell but not T cell intratumoral immune repertoire among patients with low grade appendiceal mucinous neoplasms

Abstract

Introduction: Low grade mucinous appendiceal neoplasms (LAMNs) are indolent tumors that present with widespread peritoneal metastases. Despite standard of care cytoreductive surgery and heated intraperitoneal chemotherapy (CRS-HIPEC), patients with LAMNs often recur within 1–3 years and respond poorly to chemotherapy. Methods & Results: Histopathologic review identified clusters of lymphocytes associated with epithelial hypercellularity among larger pools of mucin. Utilizing dimer avoidance multiplex-PCR and next generation sequencing, we explored the adaptive immune response in patients with recurrent LAMNs (n=10). Bulk sequencing of tumor tissue following initial CRS-HIPEC revealed a predominant expression of B cell over T cell receptors (mean expression: 0.5% Vα, 1.4% Vβ, 0.01% Vδ, 12.6% IgH, 47.6% Igκ, 37.8% Igλ). Very interestingly, we observed a heightened IgE fraction (8.4%±1.1) in patients with LAMNs, greater than both healthy donor blood (0.57%±0.36, p<0.0001, n=239) and pretreated high-grade tumors (n=66, 3.3%±2.4, p<0.0001). Although the TCR repertoire was extremely private in patients, the BCR repertoire included several shared public and private clones: 11 IgH private CDR3s shared between 2 patients, 64 Igκ public CDR3s shared among >7 patients, 261 private Igκ CDR3s shared among 3 patients, 20 public Igλ CDR3s shared among >7 patients, and 137 private Igλ CDR3s shared between 2 patients, an intriguing and unexpected finding. Conclusions: This, we believe, is the first report of adaptive immunity in low grade mucinous neoplasms that identifies a skewed but diverse infiltration of T and B cells, that warrants study in additional patients.