Tumor Immunology and Immunotherapy of Non-Small-Cell Lung Cancer

Abstract

Historically, non-small-cell lung cancer (NSCLC) has been regarded as a nonimmunogenic tumor; however, recent studies have shown that NSCLCs are among the most responsive cancers to monoclonal antibody immune checkpoint inhibitors (ICIs). ICIs have dramatically improved clinical outcomes for a subset of patients (∼20%) with locally advanced and metastatic NSCLC, and they have also demonstrated promise as neoadjuvant therapy for early-stage resectable disease. Nevertheless, the majority of patients with NSCLC are refractory to ICIs for reasons that are poorly understood. Thus, major questions are: how do we initially identify the patients most likely to derive significant clinical benefit from these therapies; how can we increase the number of patients benefiting; what are the mechanisms of primary and acquired resistance to immune-based therapies; are there additional immune checkpoints besides PD-1/PD-L1 and CTLA-4 that can be targeted to provide greater clinical benefit to patients; and how do we best combine ICI therapy with surgery, radiotherapy, chemotherapy, and targeted therapy? To answer these questions, we need to deploy the latest technologies to study tumors and their microenvironment and how they interact with components of the innate and adaptive immune systems. There is also a need for new preclinical model systems to investigate the molecular mechanisms of resistance to treatment and identify novel therapeutic targets. Recent advances in technology are beginning to shed new light on the immune landscape of NSCLC that may uncover biomarkers of response and maximize the clinical benefit of immune-based therapies. Identification of the mechanisms of resistance should lead to the identification of novel targets and the generation of new therapeutic strategies that improve outcomes for a greater number of patients. In the sections below, we discuss the results of studies examining the immune microenvironment in NSCLC, summarize the clinical experience with immunotherapy for NSCLC, and review candidate biomarkers of response to these agents in NSCLC.

Figure 1.

The cellular mediators of the innate and adaptive immune response. Hematopoietic stem cells differentiate into lymphoid and myeloid progenitors that further branch out into specific cell types mediating innate and adaptive immune response. Cells of the innate immune system provide initial response against non-self antigens, while adaptive immune response is highly specific and is mediated by the activation of lymphocytes. The cellular components of innate immunity include mast cells, basophils, eosinophils, and phagocytic cells, including dendritic cells, macrophages, and neutrophils. Soluble molecules, including complement, acute phase proteins, chemokines, and cytokines make up the humoral component of innate immunity. The cellular components of adaptive immunity include T lymphocytes (CD8⁺ and CD4⁺ [TH1, TH2, TH17, and iTREG]), B lymphocytes, and natural killer (NK) cells while immunoglobulins, chemokines, and cytokines make up the humoral component of the adaptive immune system. NK cells, neutrophils, and iTREG cell subsets overlap between both arms of immune responses. (CD) Cluster of differentiation, (TH) T helper cells, (iTREG) induced T regulatory cells.

Figure 2.

Immune checkpoint receptors expressed on immune cells and their respective ligands on antigen-presenting cells (APCs) and/or tumor cells highlighting select targetable receptors. (PD-1) Programmed cell death protein 1, (PD-L1) programmed cell death-ligand 1, (CTLA4) cytotoxic T-lymphocyte-associated protein 4, (LAG3) lymphocyte activation gene 3, (MHC-II) major histocompatibility complex-class II, (TIM3) T-cell immunoglobulin and mucin-domain containing 3.

Figure 3.

Emerging tissue-, blood-, and host-based biomarkers of potential clinical benefit or therapeutic resistance to immune checkpoint inhibitors (ICIs) under evaluation in NSCLC. (PD-L1) Programmed death-ligand 1, (TILs) tumor-infiltrating lymphocytes, (TLS) tertiary lymphoid structures, (TMB) tumor mutation burden, (TCR) T-cell receptor, (ITH) intratumoral heterogeneity, (NKs) natural killer cells, (PD-1) programmed cell death protein 1, (NLR) neutrophil-to-lymphocyte ratio, (M:L) myeloid-to-lymphoid ratio, (PLR) platelet-to-lymphocyte ratio, (ctDNA) circulating tumor DNA, (bTMB) blood tumor mutation burden.