The Microenvironment of Germ Cell Tumors Harbors a Prominent Antigen-Driven Humoral Response

Abstract

Germ cell tumors are a heterogeneous group of neoplasms derived from residual primordial tissue. These tumors are commonly found in the brain, testes, or ovaries, where they are termed germinomas, seminomas, or dysgerminomas, respectively. Like several other tumor types, germ cell tumors often harbor an immune cell infiltrate that can include substantial numbers of B cells. Yet little is known about whether the humoral immune response affects germ cell tumor biology. To gain a deeper understanding of the role B cells play in this tumor family, we characterized the immune cell infiltrate of all three germ cell tumor subtypes and defined the molecular characteristics of the B cell Ag receptor expressed by tumor-associated B cells. Immunohistochemistry revealed a prominent B cell infiltrate in the microenvironment of all tumors examined and clear evidence of extranodal lymphoid follicles with germinal center-like architecture in a subset of specimens. Molecular characterization of the Ig variable region from 320 sequences expressed by germ cell tumor-infiltrating B cells revealed clear evidence of Ag experience, in that the cardinal features of an Ag-driven B cell response were present: significant somatic mutation, isotype switching, and codon insertion/deletion. This characterization also revealed the presence of both B cell clonal expansion and variation, suggesting that local B cell maturation most likely occurs within the tumor microenvironment. In contrast, sequences from control tissues and peripheral blood displayed none of these characteristics. Collectively, these data strongly suggest that an adaptive and specific humoral immune response is occurring within the tumor microenvironment.

Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal

“…It has also been reported that the infiltrating B cells in different types of cancers are clonal and express immunoglobulins that originate from a dominant germ line gene (47)(48)(49). Here, a tumor antigen, as opposed to a transplantation antigen, may drive the infiltrating cells and possibly tumor-specific mechanisms of local "immunosuppression" are also operant.…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…In this context, it is therefore surprising that ELFs arise in tumours at all. However, ELFs have been described in numerous cancers including colorectal,60, 88 rectal,89 breast,67, 90, 91 ovarian67, 92 and germ cell93 cancers, as well as melanoma,62, 67, 94 mucosal‐associated lymphoid tissue lymphoma39 and non‐small cell lung carcinoma95, 96 (NSCLC; see Dieu‐Nosjean et al . for a comprehensive review of ELFs in cancer9).…”

Neogenesis of Lymphoid Structures and Antibody Responses Occur in Human Melanoma Metastases

“…In these tumors, molecular characterization of Ig gene rearrangements showed that clonal proliferation, somatic Ig mutation, and clonal selection all occurred (24)(25)(26). The analysis of primary germ cell cancers has revealed the presence of lymphoid follicles with germinal centers, in which ongoing antigen-driven antibody responses occurred (27). Finally, ectopic lymphoid structures have been detected in colorectal cancer, with their presence being correlated to a better prognosis (28).…”