Jabir Rizvon

Background: Due to its typically late-stage diagnoses, lung cancer is the leading cause of cancer-related deaths in the world¹ and is one of the most frequently diagnosed cancers with almost 2 million new cases each year¹¹. Late diagnoses add complexity to the treatment regimen and therefore it is of importance to improve early lung cancer screening and subsequent treatment¹. Lung cancers often propagate by manipulating immune checkpoints to evade T-cell interception⁸. Immune checkpoint inhibitors (ICIs) can be used to inhibit cancerous immune checkpoints to allow T-Cells to recognize and address cancer cells⁵. Tumor microenvironments (TMEs) have biomarkers that can serve as hallmarks for tumor presence and for therapy selection⁷. Based on these biomarkers, immune checkpoint inhibition can be selected to treat late-stage lung cancer⁷.

Objective(s): This narrative review seeks to examine the mechanism by which immune checkpoint inhibition therapy can be used to treat late-stage lung cancer.

Search Methods: The PubMed database was used as the primary data source. Search timeframe was set to 2019-2024. Keywords included “tumor microenvironment”, “immune checkpoint inhibitors”, “immune checkpoint biomarkers”, and “combination chemoimmunotherapy”.

Results: Studies show that efficacy of immune checkpoint inhibitors is highest in tumor switch pre-activated immune status³. Immune Activation Genes (IAGs) were shown to be a marker for host response to immune checkpoint inhibition³. Lung cancer patients with high levels of wild-type IAG expression had higher levels of survival probability when taking ICI therapy³. Those classified as having low levels of wild-type IAG expression had lower survivability despite ICI therapy³.  In terms of biomarkers, the CXCL13, EPSTI1, and CDK1 genes lead to specific modification of the TME including activation of neoantigens and interferon-stimulated genes¹². Studies indicated that late-stage lung cancer patients with these changes to the TME resulted in better outcomes for those being treated with ICI therapy⁴. This 3-gene signature was found to predict higher sensitivity and receptiveness to ICI treatments like PD-L1 blockade¹². Researchers honed in on the KRAS-G12D gene which is commonly mutated in lung cancers and found that a point mutation of this gene negatively correlated with PD-L1 expression¹². This point mutation further negatively correlated with certain chemokine secretions which then lead to a decrease in CD8+ Tumor infiltrating lymphocytes⁸. However, the same point mutation in the KRAS-G12D gene lead to downregulation of HMG2A via CXCL10/CXCL11 inhibition⁸. When researchers introduced Paclitaxel, a chemotherapeutic agent, it upregulated HMG2A which ultimately stimulated CD8+ T cells⁸. When combined with ICI therapy, tumor growth was significantly suppressed compared to administering ICI therapy alone⁸.

Conclusion: Immune checkpoint inhibitors best function by enabling the present immune system, not by filling in the gaps of deficient immune systems. The key is to explore and understand which genes and biomarkers predispose patients to different outcomes. Using this information, precise therapy can be implemented rather than generalized therapy with lower efficacy for late-stage lung cancer patients. Further study needs to be conducted on combination chemoimmunotherapy as a treatment for late-stage lung cancer.

Work Cited:

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2. Fehlmann T, Kahraman M, Ludwig N, et al. Evaluating the Use of Circulating MicroRNA Profiles for Lung Cancer Detection in Symptomatic Patients. JAMA Oncol. 2020;6(5):714–723. doi:10.1001/jamaoncol.2020.0001
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