Relationship Between Genetic Heterogeneity and Acquired Resistance to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: A Targeted Literature Review

OBJECTIVES: Understanding acquired resistance (AR) to immune checkpoint inhibitors (ICI) is crucial for personalised onco-therapies. Despite its importance in non-small cell lung cancer (NSCLC), evidence on the genetic and epigenetic factors of AR is limited. This study reviews recent research to fill this evidence gap.

METHODS: We conducted a targeted literature review using a Human-In-the-Loop AI tool on articles and reports from the last five years about AR to ICI in NSCLC patients. The PubMed and Google Scholar databases were searched using the keywords “genetic” AND “resistance” AND “NSCLC”. Clinical trials, observational studies, systematic reviews, and meta-analyses reporting ICI resistance in NSCLC patients were included. Studies other than ICI treatments as interventions were excluded. Two independent analysts extracted data on demographics, ICI resistance mechanisms, types of genes, and assessment methods. The data was analysed and presented in the form of tables and diagrams.

RESULTS: A total of 137 records were retrieved, with 113 excluded due to narrative reviews, population mismatch, or irrelevant outcomes, resulting in twenty-four articles for analysis. Fifteen articles identified mechanisms such as reduced T cell infiltration, PD-L1 expression, loss-of-function mutations in JAK1/2 and ß-2 microglobulin, and antigen presentation pathway alterations. Eight articles reported epigenetic modifications leading to immune evasion, while six highlighted tumour microenvironment factors like increased regulatory T cells and myeloid-derived suppressor cells (MDSCs). Assessment methods included next-generation sequencing, immunohistochemistry, and RNA sequencing. Resistance was more prevalent in patients with a smoking history and advanced-stage NSCLC.

CONCLUSIONS: This review revealed complex ICI resistance mechanisms in NSCLC patients, emphasising the need for more comprehensive genomic profiling. Understanding individual resistance mechanisms is essential for developing personalised therapies, warranting future large-scale genomic studies and integrative approaches to enhance patient-focused oncology drug development.