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.
Highlights
Cancer is a collection of diseases driven by genetic and epigenetic aberrations
Evaluation of tumor infiltrating lymphocytes (TIL) provides an estimate of the abundance of certain immune subsets which can be of prognostic value when such correlates are evident at early stages of tumors, as seen in the case of lung cancer
The repertoire of immune receptors, including immune checkpoints, found on TILs was shown to be an important regulator of maintenance of a tumor-reactive state for TILs, which improves the outcome of immune checkpoint blockade (ICB) in cancer patients
Summary
Cancer is a collection of diseases driven by genetic and epigenetic aberrations. In the classical sense, cancer pathogenesis is explained by mutations affecting proto-oncogenes and tumor suppressors, a paradigm that has proven rather simplistic with the emergence of host immune deregulation as an important hallmark in cancer pathogenesis [1]. Tumors evolve several mechanisms to evade host immune-mediated surveillance and destruction These include expansion of a local immunosuppressive microenvironment, induction of dysfunctional T cell signaling, and upregulation of inhibitory immune checkpoints which serve, under nonmalignant conditions, to keep the immune system in check by preventing an indiscriminate attack against self-cells [1]. Not all cancers have shown durable responses to immunotherapeutic intervention, whereby a number of cancers were described as being more efficiently “hidden” from host immune surveillance than others, or socalled immune “silent,” or “cold” [11, 12] These observations revealed a gap in our knowledge of the immune-biology of cancers, and sparked the emergence of a field in immunooncology that centers on delineating the immune changes during the pathogenesis of premalignant lesions and advanced tumors, in order to derive potential targets for screening, treatment, and even prediction of response to immunotherapies such as ICB. We highlight the potential translational role of immunotherapy in early management of the disease
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