The Immune Landscape of Lung Cancer
According to GLOBOCAN, lung cancer is the leading cause of cancer related mortalities world-wide. There are many different types of lung cancers, with lung cancer adenocarcinoma (LUAD) being the most predominant type. LUAD is a heterogeneous cancer with variable clinical prognosis and drug responses, with the vast majority of cases failing to respond to immune checkpoint inhibitors (ICI) despite a high tumor mutational burden (TMB).
Recent studies indicate that the presence of tertiary lymphoid structures (TLS), which are present in the tumor adjacent tissue and consist of B and T cells, are more predictive of response to ICI then TMB. TLS have been known to contribute towards various anti-tumor mechanisms, with the most prevalent being the production of anti-tumor antibodies by B-cells. The anti-tumor antibodies are produced against various tumor-associated antigens, including those belonging to the endogenous retroviruses (ERVs) that are often upregulated in cancers.
Endogenous Retroviruses as Cancer Antigens
The consequences and mechanisms of TLS resident B-cell anti-tumor activity in response to ERV antigens have remained unclear. In a recent article published in Nature, Ng et al. tackled this problem and demonstrated that B cell responses against ERV antigens are not only an essential component of anti-tumor activity, but also a strong predictor of anti-tumor response to ICI in LUAD. ERVs are remnants of ancient viruses that are integrated into the human genome and are typically inactive in normal cells. They can, however, become activated in cancers due to the changes in epigenetic landscape upon tumorigenesis.
The authors performed single cell B-cell receptor (BCR) sequencing of mouse lung tissue challenged with KRAS-mutant cancer and treated with anti-PD-L1 immunotherapy, a model they had proven to contain an ERV. They found an expansion of one B-cell clone in particular (J1KK) that targets the ERV murine leukemia virus (MLV) glycoprotein. Authors showed that the J1KK antibody produced by the B cells not only enhanced the activity of immune cells in vitro, but also extended the survival of mice with lung cancer.
ERV Antigens Promote Immunotherapy Response in LUAD
To identify the role of antibody-mediated immunity in patients with LUAD, the authors used RNA sequencing data from the Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (TRACERx) cohort with matching normal adjacent lung tissue sequences. They identified that the expression of CXCL13, which is essential for TLS formation, was associated with increased B cell infiltration into the tumor microenvironment and improved overall survival in patients with LUAD. In addition, the administration of CXCL13 along with ICI further prolonged survival, highlighting the potential of synergistic immunomodulation in patients with LUAD.
Overall, the study suggests that the combination of ICI with antibodies against ERVs could be a promising new avenue for cancer immunotherapy. One of the benefits of this approach is that ERVs are not expressed in healthy cells, thereby allowing the targeted killing of cancer cells and minimizing side effects associated with chemotherapies.
Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help
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Haider M. Hassan, Data Scientist, Bridge Informatics
Haider is one of our premier data scientists. He provides bioinformatic services to clients, including high throughput sequencing, data pre-processing, analysis, and custom pipeline development. Drawing on his rich experience with a variety of high-throughput sequencing technologies, Haider analyzes transcriptional (spatial and single-cell), epigenetic, and genetic landscapes.
Before joining Bridge informatics, Haider was a Postdoctoral Associate at the London Regional Cancer Centre in Ontario, Canada. During his postdoc, he investigated the epigenetics of late-onset liver cancer using murine and human models. Haider holds a Ph.D. in biochemistry from Western University, where he studied the molecular mechanisms behind oncogenesis. Haider still lives in Ontario and enjoys spending his spare time visiting local parks. If you’re interested in reaching out, please email jennifer.martinez@old.bridgeinformatics.com or dan.ryder@old.bridgeinformatics.com
