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Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small-Cell Lung Cancer
Biagio Ricciuti1, Giuseppe Lamberti1, Sreekar R Puchala2
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA.
Purpose:
Although immune checkpoint inhibitors (ICI) have extended survival in patients with non-small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown.
Methods:
Comprehensive tumor genomic profiling, machine learning-based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls.
Results:
We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e+ and CD8a+ T cells, and PD-L1-PD1 engagement, as well as increased distance between tumor cells and CD8+PD-1+ T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy (P = .005) and the targeted therapy (P = .01) cohorts.
Conclusion:
These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.
Insights
Acquired resistance to immune checkpoint inhibitors (ICI) in non-small-cell lung cancer (NSCLC) is linked to specific genomic mutations and reduced immune cell presence. Understanding these changes is crucial for developing new treatments to overcome resistance.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immune checkpoint inhibitors (ICI) improve survival in non-small-cell lung cancer (NSCLC).
- Acquired resistance (AR) to ICI is a significant clinical challenge in NSCLC.
- Mechanisms underlying AR to ICI in NSCLC remain largely undefined.
Purpose of the Study:
- To investigate the genomic and immunophenotypic characteristics associated with acquired resistance to ICI in NSCLC.
- To identify potential biomarkers and mechanisms driving resistance to immunotherapy in NSCLC patients.
Main Methods:
- Comprehensive tumor genomic profiling of matched pre- and post-ICI biopsies.
- Machine learning-based assessment of tumor-infiltrating lymphocytes.
- Multiplexed immunofluorescence and HLA class I immunohistochemistry (IHC).
- Comparison with control cohorts receiving chemotherapy or targeted therapies.
Main Results:
- Acquired loss-of-function mutations in genes including STK11, B2M, APC, MTOR, KEAP1, and JAK1/2 were identified in 27.8% of immunotherapy-resistant NSCLC cases.
- Significant decreases in intratumoral lymphocytes, CD3+, CD8+ T cells, and PD-L1/PD-1 engagement were observed post-ICI treatment.
- A notable decrease in HLA class I expression was found in the ICI resistance group compared to control cohorts.
Conclusions:
- Genomic and immunophenotypic heterogeneity characterizes ICI resistance in NSCLC.
- These findings underscore the need to consider diverse resistance mechanisms when designing future therapeutic strategies.
- Further research is warranted to develop novel approaches to overcome ICI resistance in NSCLC.
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