Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Abstract

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

RORc expressing immune cells negatively regulate tertiary lymphoid structure formation and support their pro-tumorigenic functions

“…The decrease in plasma cell numbers after prolonged B cell depletion may suggest the involvement of an anti-tumor antibody response. Indeed, recent studies highlight the contribution of TLS-residing B cells to anti-tumor response through the production of tumor-binding antibodies and involves antibody-dependent cellular cytotoxicity (Ng et al, 2023). Understanding the effect of B cell depletion in IKK RORc KO mice is more complicated since it also reduced TLS numbers which directly affect iCCA formation.…”

Caspase 8 protects pancreatic neoplasia from KRAS-driven necroptotic priming

“…2c). Interestingly, absence of caspase 8 specifically increased the overall B-cell, and in particular plasma cell compartment, a cell type associated with anti-tumor immunity 17,31 (Extended Data Fig. 2d).…”

Subtype-specific HERV-K102 envelope is a novel serum immunosuppressive biomarker and therapeutic target of cancer

“…Previous studies have revealed that HERV-K-Env proteins are enriched in tumor tissues of a variety of cancers [11][12][13][14][15][16], and there are a number of HERV-K family members, but it is unknown whether K-Env proteins are present in circulating blood of patients with cancer. Of the HERV-K family, only HERV-K108 and HERV-K102 proviruses contain intact ORFs [10], thus, we focused on K108-Env and K102-Env in this study.…”

“…Several HERV-K family members, such as HERV-K102 and HERV-K108, are unique to humans and continue to evolve [9,10]. We, and other researchers, have previously demonstrated that HERV-K envelope glycoproteins (K-Env), which consist of a surface unit (SU) and a transmembrane (TM) subunit with potential immunosuppressive activity, are enriched in tumor tissues and correlate with poor outcome in cancers that include acute myeloid leukemia (AML), pancreatic duct adenocarcinoma (PDAC), lung cancer, and glioma [11][12][13][14][15][16]. Previous studies have shown that reactivation of HERV-K is associated with immunosuppressive status in some diseases.…”