EGFR‐targeted therapy alters the tumor microenvironment in EGFR‐driven lung tumors: Implications for combination therapies

Abstract

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD‐1/PD‐L1) pathway have profoundly improved the clinical management of non‐small‐cell lung cancer (NSCLC). Nevertheless, the superiority of single‐agent PD‐1/PD‐L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR‐driven lung tumor models to investigate dynamic microenvironmental responses to EGFR‐TKI treatment. We observed that at an early stage, sensitive EGFR‐TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8+ T cells and dendritic cells, eradication of Foxp3+ Tregs, and inhibition of M2‐like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune‐mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid‐derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR‐TKIs increased the levels of IL‐10 and CCL‐2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR‐TKIs in vivo. The results have implications for combination therapy using EGFR‐TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

“…Furthermore, preclinical results have shown that EGFR activation can upregulate intrinsic PD-L1 expression on tumor cells, which induces T cell apoptosis and contributes to the immune escape of EGFR-mutant NSCLC. In addition, EGFR-TKIs can potentiate the induction of MHC class I and II molecules in response to IFN-γ and enhance T cell-mediated tumor killing [47]. In this regard, these studies provide a theoretical basis to support the potential synergistic effects of combining PD-1/PD-L1 inhibitors and EGFR-targeted therapy in NSCLC patients carrying EGFR mutations accompanied by upregulation of PD-L1 expression.…”

“…Changes in expression of membranous immunomodulatory molecules in the TME and release of immunosuppressive soluble factors, such as TGF-β, IL-10 and adenosine (ADO) [47,48], play a crucial role in tumor progression.…”

“…Several reports have reported that the tumor microenvironment (TME) [31][32][33][34][35][36], tumor immunogenicity [37][38][39], tumor-specific mutations, copy number variants [40,41] and abundances of specific intestinal bacteria can [42] affect the efficacy of ICIs. Multiple studies have demonstrated that EGFR mutations in NSCLC are more likely to correlate with an immunosuppressive TME [41,[43][44][45][46][47][48], the tumor mutation burden (TMB) [43,49], and expression of PD-L1 [41,[50][51][52][53]. In addition, EGFR-TKIs may modulate the immune response by regulating TME.…”

“…Immunosuppressive effects of EGFR mutations have also been described in recent years. Several studies have reported that EGFR mutations can modulate possible factors related to the status of the TME, such as tumorinfiltrating lymphocytes (TILs) [41,43,65], Tregs [45,66], MDSCs [47,67] tumor-associated macrophages (TAMs) [47], immunoregulatory cytokines [47,48] and exosomes [68]. These preclinical and clinical findings suggest that the TME of NSCLC patients with EGFR mutations may be unique, differing from patients with wildtype EGFR, and that EGFR mutations may impact the antitumor immune response by affecting the TME (Fig.…”

FGL2 is positively correlated with enhanced antitumor responses mediated by T cells in lung adenocarcinoma

“…EGFR-targeted therapy such as EGFR tyrosine kinase inhibitors (EGFR-TKIs) alters the tumor microenvironment in lung cancer (Matsumoto et al, 2019). EGFR-TKIs could increase cytotoxic CD8 + T cells and dendritic cells in the tumor environment of lung cancer (Jia et al, 2019). FGL2 also increase cytotoxic CD8 + T cells and dendritic cells in the tumor environment of lung cancer.…”