Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

Abstract

Lung cancer is the number one cause of cancer-related deaths. The malignancy is characterized by dismal prognosis and poor clinical outcome mostly due to advanced-stage at diagnosis, thereby inflicting a heavy burden on public health worldwide. Recent breakthroughs in immunotherapy have greatly benefited a subset of lung cancer patients, and more importantly, they are undauntedly bringing forth a paradigm shift in the drugs approved for cancer treatment, by introducing "tumor-type agnostic therapies". Yet, and to fulfill immunotherapy's potential of personalized cancer treatment, demarcating the immune and genomic landscape of cancers at their earliest possible stages will be crucial to identify ideal targets for early treatment and to predict how a particular patient will fare with immunotherapy. Recent genomic surveys of premalignant lung cancer have shed light on early alterations in the evolution of lung cancer. More recently, the advent of immunogenomic technologies has provided prodigious opportunities to study the multidimensional landscape of lung tumors as well as their microenvironment at the molecular, genomic, and cellular resolution. In this review, we will summarize the current state of immune-based therapies for cancer, with a focus on lung malignancy, and highlight learning outcomes from clinical and preclinical studies investigating the naïve immune biology of lung cancer. The review also collates immunogenomic-based evidence from seminal reports which collectively warrant future investigations of premalignancy, the tumor-adjacent normal-appearing lung tissue, pulmonary inflammatory conditions such as chronic obstructive pulmonary disease, as well as systemic microbiome imbalance. Such future directions enable novel insights into the evolution of lung cancers and, thus, can provide a low-hanging fruit of targets for early immune-based treatment of this fatal malignancy.

Keywords: anti-tumor immunity; immunogenomics; immunotherapy; lung cancer; lung premalignancy; non-small cell lung cancer.

Figure 1

A proposed model for the malignant transformation of normal tissue with emphasis on the immune microenvironment. The events underlying this process are explained in the text. Normal cells are in blue; preneoplastic cells in violet; transformed cells in pink; and malignant cells in green. Upper panel: Normal cells accumulate somatic mutations in driver genes leading to the formation of premalignant cells. Those preneoplastic cells attract the immune system, wherein cells from both the innate and adaptive immune system infiltrate the tissue. Certain tumor cells evolve several mechanisms to evade host immune-mediated surveillance and destruction. Clinical inhibition of immune-checkpoints blocks checkpoint inhibitory action and re-activates the immune system to launch an attack on tumor cells. Lower panel: Smoking induces an extensive mutational repertoire leading to the formation of transformed cells. Many of the immune molecules and cells that participate in the elimination phase have been characterized, but future work is required to determine their exact sequence of action. In addition, further studies are warranted to understand the sequence of events that render a subset of smokers more prone to develop lung cancer compared to others who do not develop this malignancy throughout their lifetime.