Abstract
High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.
Highlights
Lung cancer is the leading cause of cancer-related mortality in the US [1]
We previously showed that targeting estrogen receptor β (ERβ) with the ER blocker fulvestrant (F), together with targeting the family of epidermal growth factor receptors (HERs) with the pan-HER tyrosine kinase inhibitor (TKI) dacomitinib (D), had a synergistic antitumor effect in ERβ+ lung cancer, producing a gene signature that better predicts clinical outcomes [7]
F and D with anti-programmed death-1 (PD-1) in a sequential approach is supported by the ability of F+D to induce potent cancer cell death, downregulate the ER/HER gene expression network in tumor cells, enhance immune cell infiltration, and promote a relatively inflamed tumor microenvironment (TME) with increased PD-1 expression
Summary
Lung cancer is the leading cause of cancer-related mortality in the US [1]. Despite the advancements in understanding its biology, the 5-year survival rate is less than 20% [2].Current treatment for advanced non-small cell lung cancer (NSCLC) relies on cytotoxic chemotherapy, targeted therapies, and immune-checkpoint blockade. Lung cancer is the leading cause of cancer-related mortality in the US [1]. Despite the advancements in understanding its biology, the 5-year survival rate is less than 20% [2]. Current treatment for advanced non-small cell lung cancer (NSCLC) relies on cytotoxic chemotherapy, targeted therapies, and immune-checkpoint blockade. The tumor microenvironment (TME) is a key determinant of lung tumor progression, and the reciprocal cross-talk between tumor cells and immune cells in the TME plays a crucial role in controlling tumor fate. Tlymphocytes play a major role in the antitumor immune response. The PD-1/PD-L1 inhibitory immune checkpoint pathway represents the major immune-escape mechanism for tumors, and agents that target this pathway have redefined the standard of care treatment of NSCLC. The overall response rate for PD-1/PD-L1 inhibitors, when used as a monotherapy, is less than 30% [6]
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