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TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer
Teng Li1, Han Wang2, Jiachen Xu3
1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Background:
Resistance or even hyper-progression to immune checkpoint inhibitors (ICIs) manifesting as accelerated disease progression or death has impeded the clinical use of ICIs. The transforming growth factor beta (TGFβ) receptor pathway has been identified in contributing to immune dysfunction, which might be associated with resistance to ICIs. We aimed to explore the role of TGFβ in the resistance to ICIs in non-small cell lung cancer (NSCLC) in this study.
Methods:
Public cohorts with patients treated with ICIs or chemotherapy including POPLAR/OAK (n = 853), MSKCC (n = 1662) and Van Allen (n = 57) and TCGA (n = 3210) cohorts were obtained and analyzed.
Results:
The expression of immune-checkpoint related genes, including programmed death-ligand 1 (CD274), lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death ligand 1 (PDCD1), and programmed cell death 1 ligand 2 (PDCD1LG2) were significantly upregulated in transforming growth factor beta TGFβ receptor 2 (TGFβR2)-mutated patients than those with wild-type TGFBR2 (p < 0.05). In the POPLAR/OAK cohort, TGFBR2-mutated patients showed shorter progression-free survival (PFS) [ p = 0.004; hazard ratio (HR), 2.83; 95% confidence interval (CI), 1.34-6.00] and overall survival (OS) ( p = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than those with wild-type TGFBR2 when treated with ICIs but not chemotherapy. In the merged MSKCC and Van Allen cohorts, a similar result was observed that the OS was inferior in patients with mutated TGFBR2 compared with those with wild-type TGFBR2 (p = 0.007; HR, 2.53; 95% CI, 1.25-5.12). The association between TGBFR2 mutation and survival remained significant in multivariable cox regression in both POPLAR/OAK cohort (p = 0.02; HR, 2.53; 95% CI, 1.17-5.45) and merged cohort (p = 0.008; HR, 2.63; 95% CI, 1.29-5.35). We further evaluated the association between TGFBR2 mutations and OS in multiple types of tumors. The association between TGFBR2 mutations and OS remained significant in NSCLC (p = 0.02; HR, 2.47; 95% CI, 1.16-5.26), but not in other type of tumors.
Conclusions:
We identified that TGFBR2 mutation predicted the resistance to ICIs in NSCLCs. The clinical delivery of ICIs should be cautious in those patients.
Insights
Transforming growth factor beta receptor 2 (TGFβR2) mutations predict resistance to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Patients with TGFβR2 mutations showed poorer survival outcomes with ICIs, suggesting caution in their clinical use.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy due to resistance and hyper-progression.
- The transforming growth factor beta (TGFβ) receptor pathway is implicated in immune dysfunction and potential ICI resistance.
Purpose of the Study:
- To investigate the role of TGFβ signaling in ICI resistance within non-small cell lung cancer (NSCLC).
Main Methods:
- Analysis of public patient cohorts (POPLAR/OAK, MSKCC, Van Allen, TCGA) treated with ICIs or chemotherapy.
- Evaluation of gene expression and survival outcomes based on TGFβ receptor 2 (TGFβR2) mutation status.
Main Results:
- TGFβR2-mutated NSCLC patients exhibited significantly upregulated immune-checkpoint related genes.
- Patients with TGFβR2 mutations had shorter progression-free survival and overall survival when treated with ICIs, but not chemotherapy.
- TGFβR2 mutations were significantly associated with inferior overall survival in NSCLC patients treated with ICIs.
Conclusions:
- TGFβR2 mutation status is a predictive biomarker for ICI resistance in NSCLC.
- Clinical application of ICIs in NSCLC patients with TGFβR2 mutations requires careful consideration.
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