Narrative review of the pathologic assessment of immune response in lung cancer

Lung cancer is the most common cause of cancer death worldwide. While targeted therapies have offered promise for a small subset of patients with driver mutations, usually found among light/neversmokers, the majority arise among heavy smokers are usually not benefited. Immune checkpoint inhibition has instead offered greater promise in this larger cohort of patients. This observation has led to greater attention to the immune components of the tumor microenvironment (TME) and a model of tumor immunoediting has emerged in which cancer evolves through phases of elimination, equilibrium, and escape. The chief effector cell in this process is the cytotoxic T-cell (CTL) which can be measured quantitatively using immunohistochemistry for CD8. While the density of this population within primary tumors and their metastasis is prognostic in advanced stage disease of both small cell lung carcinoma (SCLC) and nonsmall cell lung cancer (NSCLC), the prognostic significance is more variable in early stage disease and in particular among adenocarcinoma (LUAD) which are heterogenous in their morphology, biology, and risk factor associations. The anti-tumor role of CTL is dependent on a host of immune cell interactions which can be measured by assessing tumor-infiltrating lymphocytes (TIL) on routine H&E staining as well as specific dendritic cell populations associated with the formation of tertiary lymphoid structures (TLS) using immunohistochemistry for LAMP or regulatory T-cells (Treg) using FoxP3. Finally, tumor associated macrophages (TAM) and neutrophils (TAN) may polarize to promote (M1 or N1) or inhibit (M2 or N2) CTL effectiveness and can be measured using a variety of immunohistochemical approaches. Herein we review the immunopathologic features of TME in lung cancer and their prognostic associations.