Targeting the Lung Cancer Microenvironment: Harnessing Host Responses

Abstract

Understanding the host response to lung cancer is critical in the development of long-term therapeutic responses and cures for advanced-stage disease. While state-of-the-art treatments that target the tumor cell directly are effective as initial antitumor approaches, strategies that augment antitumor host responses are highly appealing, and may overcome resistance through novel discoveries. These involve (1) discovery of basic mechanisms by which the tumor “hijacks” host immune regulation and vascular homeostasis (thus promoting tumor growth), and (2) discovery of tumor-resistance pathways that counter immune- and/or vascular-targeting therapies. Major mechanisms by which lung carcinoma is able to usurp host mechanisms include both the tumor’s manipulation of immune checkpoint regulatory pathways (with a cytokine and dendritic cell balance that maintains a high suppressor/effector T-cell ratio) and the remodeling of blood and lymphatic vasculature by multiple endothelial mitogens, thereby promoting tumor growth and dissemination. Lymphatic dissemination in particular involves not only tumor cells but also immunosuppressive dendritic cell trafficking to tumor-draining lymph nodes. Novel approaches to overcome these challenges include immune checkpoint-blocking strategies (e.g., PD-1/PD-L1 or CTLA4 blockade which inhibit T-effector suppression) or agonists to T-stimulatory pathways, such as OX40 or 4-1BB. They also include vaccine development and/or approaches to manipulate dendritic cells or engineer T cells (e.g., CAR-T cells) against antigens that are (preferably) clonally expressed by the entire tumor. Major limitations to these approaches include poor tumor-antigen recognition or presentation by dendritic cells or hyporesponsive T cells in the immunosuppressive tumor microenvironment. Moreover, autoimmune-type side effects of immune checkpoint T-cell targeting or T-cell engineering present therapeutic challenges. Finally, the discovery of tumor neo-antigens, which are known to be more abundantly expressed in tumors initiated by environmental stimuli (e.g., melanoma or squamous lung carcinoma), as well as their ability to predict T cell responsiveness, is another important development in the quest to augment host immune responses to lung cancer. These discoveries will be valuable in promoting a set of strategies that markedly improve the chances for durable remissions or cures in the setting of advanced-stage lung cancer or even recurrent disease following definitive treatments.