Tumour- and Non-Tumour-Associated Factors That Modulate Response to PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer

Abstract

The interaction of programmed cell death receptor 1 (PD-1) on the surface of immune cells with its ligand, programmed cell death ligand 1 (PD-L1), expressed on tumour cells and antigen-presenting cells, leads to tumour immune evasion. Antibodies that target either PD-1 or its ligand PD-L1 have shown a favourable response in cancer patients, especially those with non-small cell lung cancer (NSCLC). However, only 15 to 25% of advanced NSCLC patients will benefit from immunotherapy. The PD-L1 tumour proportion score (TPS) is the current standard biomarker to select patients for PD-1/PD-L1 blockade therapy, as patients with a high PD-L1 TPS show better response compared to patients with a low PD-L1 TPS. However, since PD-L1 expression is a continuous variable and is an imperfect biomarker, investigation into additional predictive markers is warranted. This review focuses on tumour- and non-tumour-associated factors that have been shown to affect the response to PD-1/PD-L1 inhibitors in NSCLC. We also delve into mechanistic and clinical evidence on these potential biomarkers and their relationship to the tumour microenvironment (TME).

Keywords: NSCLC; PD-1; PD-L1; immune checkpoint inhibitors; patient response.

Figure 1

LKB1 Dependent Signalling. LKB1 directly phosphorylates and activates AMP-activated protein kinase in nutrient-deficient and hypoxic conditions; in turn, AMPK phosphorylates the TSC2 complex to mediate the effects on cell growth. AMPK activation, therefore, suppresses mTORC1-dependent transcriptional regulators, such as MYC, HIF1α, and cyclin D, which play a role in promoting cell growth and tumourigenesis. Conversely, when LKB1 is mutated, it does not lead to the successful activation of AMPK in low intracellular ATP conditions. This will prevent the activation of tumour suppressors TSC1/TSC2, leading to constant hyperactivation of the mTORC1 complex. mTORC1 then promotes tumourigenesis via the transcriptional activation of MYC, HIF1α, and cyclin D. LKB1 alterations also modulate the tumour immune microenvironment by increasing immune suppressive subsets and reducing the infiltration of CD4⁺/CD8⁺ T cells. LKB1: liver kinase B1, TSC1/1: tuberous sclerosis complex 1/2, mTORC1: Mammalian Target of Rapamycin Complex 1, HIF1α: Hypoxia-Inducible Factor.

Figure 2

KEAP1-dependent signalling. In normal circumstances, NRF2 interacts with two KEAP1 molecules via the ETGE and DLG motifs in its Neh2 domain to cause NRF2 ubiquitination via the activation of the Cul3-based E3 ligase complex [51]. After its ubiquitination, NRF2 is marked for degradation by the 26S proteosome, with low cytoplasmic levels. When cells are exposed to oxidative stress or cytotoxic drugs, such as chemotherapies, sensor cysteines in KEAP1, especially Cy151, interact with electrophiles and ROS, causing conformational changes and resulting in the detachment of NRF2 from KEAP1 and the disruption of KEAP1-mediated NRF2 degradation [52]. This reduces the binding affinity between the two proteins, allowing NRF2 to translocate to the nucleus to activate the transcription of various protective genes. Once oxidative stress is removed, KEAP1 translocates to the nucleus and brings NRF2 out to the cytoplasmic Cul-E3 ubiquitin ligase complex for degradation [51].

Figure 3

Relationship between hypoxia and angiogenesis. A hypoxic TME will lead to the activation and stabilization of hypoxia-inducible transcription factors (HIFs), especially HIF-1α, which directly binds to the PD-L1 promoter to upregulate its expression and also plays a role in angiogenesis. HIF-1α directly upregulates VEGF, leading to the formation of new blood vessels, which increase the oxygen and nutrient supply to the tumour. Additionally, angiogenesis also leads to greater infiltration of immune cells, especially regulatory T cells, MDSCs, and TAMs, hence contributing to the immunosuppressive TME. Bevacizumab, an anti-VEGF, can inhibit the binding of VEGF to its receptor VEGF-R and prevent the formation of new blood vessels and, by extension, an immunosuppressive TME. MDSCs: myeloid-derived suppressor cells. TAMs: tumour-associated macrophages. TME: tumour microenvironment.

Figure 4

Tumour-associated and non-tumour-associated factors that confer response to ICIs in NSCLC.