Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments

Abstract

Non-small cell lung cancer (NSCLC) is the most common lung cancer diagnosis, among which epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and anaplastic lymphoma kinase (ALK) mutations are the common genetic drivers. Their relative tyrosine kinase inhibitors (TKIs) have shown a better response for oncogene-driven NSCLC than chemotherapy. However, the development of resistance is inevitable following the treatments, which need a new strategy urgently. Although immunotherapy, a hot topic for cancer therapy, has shown an excellent response for other cancers, few responses for oncogene-driven NSCLC have been presented from the existing evidence, including clinical studies. Recently, the tumor microenvironment (TME) is increasingly thought to be a key parameter for the efficacy of cancer treatment such as targeted therapy or immunotherapy, while evidence has also shown that the TME could be affected by multi-factors, such as TKIs. Here, we discuss changes in the TME in NSCLC after TKI treatments, especially for EGFR-TKIs, to offer information for a new therapy of oncogene-driven NSCLC.

Keywords: ICIs - immune checkpoint inhibitors; driver mutation; non-small cell lung cancer; tumor microenvironment; tyrosine kinase inhibitor.

Figure 1

TME in NSCLC with EGFR mutation is presented as a phenotype of immunosuppression. EGFR signal upregulates expression of PD-L1 via PI3K-AKT, RAS-RAF-MEK-ERK, JAK-STAT3, and PI3K/AKT pathways, which further inhibit CD8+ T cells. The downregulation of CXC-chemokine ligand 10 (CXCL10) also recruits less CD8+ T cells. EGFR signal upregulates (CXCL22) and CC-chemokine ligand 5 (CCL5) resulting in the increase of Tregs. Adenosine as the immune-suppressive factor could be observed to be overproduced in EGFR-mutated cancer cells, which can directly suppress the process of NK cell killing, DC maturation, the function of macrophages, and the function and proliferation of cytotoxic T cells. A complex interplay also exists between different components of TME: DCs could impair the proliferation of CD8+ T cells. Tregs can actively attenuate and subvert the antitumor immune responses of CD8+ T cells by secreting cytokines such as TGF-β, IL-10, and IL-35. A high expression level of PD-L1 on M2 TAMs restricts the antitumor activity of CD8+ T cells. TGF-β secreted by M2 TAMs can also directly suppress the process of NK cell killing. Moreover, exosomes can repress the function of DCs and the proliferation of CD8+ T cells. TME, tumor microenvironment; NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; NK, natural killer; DC, dendritic cell; TAM, tumor-associated macrophage.

Figure 2

TME in NSCLC with EGFR mutation changed with treatments of TKIs, which is presented as more immunostimulatory. EGFR-TKIs may decrease the expression of PD-L1 via blocking NF-κB, ERK, and STAT. Generally, a higher CD8+ T-cell infiltration in the TME after TKI treatment is concurrent with a higher CXCL10 expression. CD8+ T cells changed with treatment period and sensitivity: earlier, the number of CD8+ T cells elevated and later remained unchanged. Also, the infiltration of CD8+ T cells elevated upon sensitive TKI treatments while decreased upon resistance. The infiltration and function of Tregs were significantly reduced by inhibiting the GSK-3β pathway concurrent with downregulated CCL22. Tregs also changed with treatment period and sensitivity: earlier, the number of Tregs decreased and later remained unchanged. The number of Tregs decreased upon sensitive TKI treatments while elevated upon resistance. Upregulation of B cells is detected after TKI treatment. CD4+ T cells involved in the antitumor activity are mostly increased by TKIs with increasing TNF-α and IL-2. The interaction between NK cells and human lung cancer cells was enhanced by TKI via upregulation of NKG2D on NKs and NKG2D ligands, such as ULBP1, ULBP2, and MICA on tumor cells. A high degree of DC infiltration concurrent with a higher MHC class II expression on their surfaces was obtained after TKIs. The abundance of M1-TAMs is usually upregulated by TKIs at earlier but downregulated later. However, M2-TAMs usually tend to decrease and even shift to M1-TAMs by TKIs. TME, tumor microenvironment; NSCLC, non-small cell lung cancer; EGFR TK2, epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors; DC, dendritic cell; TAM, tumor-associated macrophage.