In a study that examined matched samples before and after treatment with immune checkpoint inhibitor (ICI) from patients with non-small cell lung cancer (NSCLC) who developed acquired resistance to ICI, the researchers identified recurrent acquired genomic changes, decreased tumour-infiltrating lymphocytes (TILs) and HLA class I expression in tumour biopsies at disease progression on ICI, not seen in patients treated with chemotherapy or targeted therapies.
The 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 according to Dr. Mark M. Awad of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute in Boston, MA, US, and colleagues who published the findings on 11 January 2024 in the JCO.
The authors explained in the background that a landscape of acquired resistance to ICI in NSCLC remains unknown. Recent reports have identified defects in INFγ signalling and impaired HLA class I antigen presentation as potential mechanisms of acquired resistance to ICI in solid tumours. However, these studies were limited by the retrospective design, small sample sizes, and the lack of a control group. Although rational strategies have been developed to overcome resistance to targeted therapies, there are no approved immunotherapies to overcome resistance to ICI in NSCLC.
The study team performed a comprehensive tumour genomic profiling, machine learning-based assessment of TILs, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) on matched pre- and post-ICI tumour biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed acquired resistance to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls.
The comprehensive genomic profiling and immunophenotypic characterisation were performed on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies. The findings were compared with a control cohort of patients with non-ICI intervening therapies between biopsies of whom 32 received chemotherapy, 89 targeted therapies and 17 both.
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 intratumoural lymphocytes, CD3e-positive and CD8a-positive T cells, and PD-L1-PD1 engagement, as well as increased distance between tumour cells and CD8-positive, PD1-positive T cells.
There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of acquired resistance compared with chemotherapy (p = 0.005) and the targeted therapy (p = 0.01) cohorts.
Previous studies have shown that loss-of-function mutations in STK11, KEAP1, and SMARCA4 drive primary resistance to ICI in lung cancer. In the latest article published in the JCO, the study team demonstrated that these alterations can also mediate acquired resistance to ICI. This is significant as these mutations create vulnerabilities exploitable by novel therapies to restore ICI sensitivity.
Additionally, 6.3% of patients acquired B2M mutations, which resulted in abolished B2M expression by IHC in 50% of evaluable cases. Although the results are supportive for mechanistic role of B2M loss in mediating acquired resistance to ICI, these findings should be interpreted with caution, given the small sample size.
Additionally, the study team found an acquired biallelic loss of JAK1, as well as an acquired homozygous deletion in JAK2. JAK1 and JAK2 are essential signal transducers of the INFγ pathway, therefore, in the setting of acquired resistance to ICI, a tumour may become insensitive to INFγ because of loss of JAK1/2.
Other acquired genomic alterations previously associated with an impaired antitumour immune response through the activation of the MAPK, PI3K/Akt/mTOR, and wingless type/β-catenin pathways were observed among patients with acquired resistance to ICI but not among those who were treated with chemotherapy. These included activating mutations in PIK3CA, SOS1, ERBB2, and BRAF, and loss-of-function mutations in NF1/NF2 and APC.
Drugs targeting these pathways are either already approved or under investigation, and preclinical evidence has shown that PI3K/Akt/mTOR and MAPK inhibition may synergise with immunotherapies to resensitise resistant tumours to ICI. These results remain exploratory and preclinical validation is necessary.
Finally, the study team demonstrated decreased TILs and HLA class I expression at the time of acquired resistance to ICI. Reduced HLA expression has been recognised as a mechanism of escape from antitumour immunity, and the most common mechanisms of HLA-I losses are reversible defects that can be pharmacologically exploited to restore HLA expression.
Although limitations of this study include the heterogeneity and the small sample size of some subgroups, the authors concluded that mechanisms of acquired resistance to ICI are heterogeneous and require personalised post-ICI strategies.
The findings were previously presented in part at ASCO 2022 Annual Meeting (3-7 June; Chicago, IL, US) and at the Society for Immunotherapy of Cancer 2022 Congress (8-12 November; Boston, MA, US).
This work was supported by the Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research and LUNGSTRONG.
Reference
Ricciuti B, Lamberti G, Puchala SR, et al. Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non–Small-Cell Lung Cancer. JCO; Published online 11 January 2024. DOI: https://doi.org/10.1200/JCO.23.00580
