Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas

Abstract

Background: Programmed death-ligand 1 (PD-L1) expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression is largely unknown and may improve prediction of response to ICI. Patients and methods: We evaluated patients with lung adenocarcinoma for whom PD-L1 testing and targeted nextgeneration sequencing (using MSK-IMPACT) was performed on the same tissue sample. Clinical and molecular features were compared across PD-L1 subgroups to examine how molecular phenotype associated with tumor PD-L1 expression. In patients treated with anti-PD-(L)1 blockade, we assessed how these interactions impacted efficacy. Results: A total of 1586 patients with lung adenocarcinoma had paired PD-L1 testing and targeted next-generation sequencing. PD-L1 negativity was more common in primary compared to metastatic samples (P < 0.001). The distribution of PD-L1 expression (lymph nodes enriched for PD-L1 high; bones predominantly PD-L1 negative) and predictiveness of PD-L1 expression on ICI response varied by organ. Mutations in KRAS, TP53, and MET significantly associated with PD-L1 high expression (each P < 0.001, Q < 0.001) and EGFR and STK11 mutations associated with PD-L1 negativity (P < 0.001, Q ¼ 0.01; P ¼ 0.001, Q < 0.001, respectively). WNT pathway alterations also associated with PD-L1 negativity (P ¼ 0.005). EGFR and STK11 mutants abrogated the predictive value of PD-L1 expression on ICI response. Conclusion: PD-L1 expression and association with ICI response vary across tissue sample sites. Specific molecular features are associated with differential expression of PD-L1 and may impact the predictive capacity of PD-L1 for response to ICIs.

Immune modulatory effects of oncogenic KRAS in cancer

“…Later, the mechanism causing KRAS to upregulate PD-L1 was shown to be through increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP), mediated by downstream MEK signalling 62 . The evaluation of patients with LAC showed a strong association between KRAS mutations and high PD-L1 expression 63 , which is contrasting to reports in CRC 64 . Canon and colleagues described the potential of combining the novel KRAS G12C inhibitor AMG 510 with immune-checkpoint inhibitors, and showed that the combination of AMG 510 with anti-PD-1 blockade induced tumour cell killing, and improved the sensitivity of the TME to immunotherapy 65 .…”

Clinically relevant prognostic and predictive markers for immune-checkpoint-inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC)

“…the expression of PD-L1 seems to be lower in primary tumor samples than in metastases. This indicates that an advanced disease may be more likely to express PD-L1 than an earlier stage disease [22]. the extent of PD-L1 expression in metastases varies modestly by anatomic site.…”

“…Tumor-cell-intrinsic oncogenic pathways including STK11/LKB1 and KEAP1 are associated with a "cold", non-T cell-inflamed TME, thus significantly impairing clinical responses to ICI treatment [22,63,64,161,162]. The inactivation of STK 11 increases production of G-CSF, CXCL7 and IL-6, which recruit tumor-associated neutrophils that in turn increase T-cell dysfunction via arginase A and IL-10 release [22,162]. Along with that, this genomic alteration has been identified as a major driver of de-novo resistance to PD-1 axis resistance in KRAS-positive lung adenocarcinoma [63].…”

“…the extent of PD-L1 expression in metastases varies modestly by anatomic site. The proportion of cases with "PD-L1 high expression" was greatest in lymph nodes (30% PD-L1 high) and least in bone (16% PD-L1 high), so lymph node sampling may require an adjusted scale [22]. among patients with primary tumor tissue sampling, there was lower PD-L1 expression when resection specimens were used compared to biopsy samples [22].…”

Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future

“…Studies on the predictive importance of KRAS mutations for the efficacy of immune checkpoint inhibitors have not uniformly provided positive results. Mutant KRAS was associated with increases in tumor infiltrating lymphocytes, PD-L1 expression and tumor mutational burden [ 182 , 183 ]. However, while Gianoncelli et al observed no significant differences between KRAS + and non- KRAS NSCLC patients in terms of progression-free or overall survival [ 184 ], Kauffmann-Guerrero et al reported a positive outcome for KRAS mutations in response to immune checkpoint inhibitors [ 185 ].…”