Anti-PD-L1/VEGF combination shows limited immune efficacy in EGFR-TKI-naïve Egfr-mutant lung cancer models.

Immune checkpoint inhibitors (ICIs) have limited efficacy in EGFR-mutant lung adenocarcinoma due to its intrinsically non-inflamed tumor microenvironment (TME). While quadruple therapy combining chemotherapy, anti-PD-L1, and anti-VEGF antibodies has shown inconsistent results in EGFR-tyrosine kinase inhibitor (TKI)-pretreated patients, the role of anti-VEGF therapy in modulating this non-inflamed TME in TKI-naïve settings remains unclear. Understanding this gap is crucial for developing effective immunotherapeutic strategies for this patient population.

Researchers utilized an EGFR-TKI-naïve syngeneic Egfr-mutant mouse model to evaluate the effects of anti-VEGF, anti-PD-L1, carboplatin, and paclitaxel. These agents were tested as monotherapies and in various combinations. Tumor microenvironment analysis was conducted using immunohistochemistry (IHC), flow cytometry, and RNA sequencing. The study also included CD8+ T-cell depletion experiments to investigate specific immune mechanisms. A "low-dose anti-VEGF" was specifically mentioned in combination with paclitaxel.

Anti-PD-L1 monotherapy demonstrated no antitumor effect in the Egfr-mutant mouse model. Crucially, adding anti-VEGF therapy failed to convert the non-inflamed tumor microenvironment to an inflamed status. While paclitaxel—but not carboplatin—combined with low-dose anti-VEGF inhibited tumor growth, adding anti-PD-L1 to this combination provided no additional benefit. This indicates the specific anti-VEGF-A antibody evaluated here has a limited role in sensitizing tumors to anti-PD-L1, regardless of chemotherapy. Further investigation revealed that CD8+ T-cell depletion did not attenuate the effect of paclitaxel plus low-dose anti-VEGF. IHC and RNA sequencing data showed increased natural killer cell infiltration, suggesting a CD8+ T-cell-independent, innate immune mechanism at play. > These findings provide preclinical evidence that the evaluated anti-VEGF has limited immunomodulatory activity in EGFR-TKI-naïve Egfr-mutant tumors with a non-inflamed TME.