NSCLC Pathophysiology

Great strides have been made in delineating the molecular events that lead to non-small cell lung carcinoma (NSCLC), but a complete understanding of the pathogenesis continues to evolve. Historically, NSCLC has been considered a nonimmunogenic disease; however emerging evidence has demonstrated that the lack of an effective immune response is functional, rather than structural in nature.¹

The adaptive anticancer immune response is initiated by immature dendritic cells (DCs), which are found in most tumors in humans and capable of capturing antigens released from cancer cells.¹ Immature DCs subsequently undergo maturation and migrate to tumor-draining lymph nodes, presenting tumor antigens within major histocompatibility complex (MHC) molecules to naïve T cells (Figure 3). This triggers a protective T-cell response composed of specific CD4+ helper T (Th) cells and CD8+ cytotoxic T cells. T-cell activation requires interaction not only between the antigen-MHC complex on DCs and T-cell receptors but also among an array of co-stimulatory molecules, including CD80/86 on DCs and the CD28 receptor on T cells. The activated cytotoxic T cells infiltrate the tumor, thereby recognizing and killing tumor cells directly in an MHC-restricted fashion. Additionally, cytokines are secreted by the activated Th cells inducing inflammation and recruiting other immune cells to the tumor microenvironment to eliminate cancer cells. DCs also induce B-cell mediated antibody responses and nature killer (NK) cell activity.

The complex relationship between the immune system and cancer can be described by the hypothesis of cancer immunoediting, which encompasses the dynamics of tumor development over time.²The immune system via immune surveillance can destroy transformed and/or malignant cells.^2,3 However, immune surveillance is not always successful, resulting in ‘edited’ tumors that have escaped immune surveillance.

Cancer immunoediting is composed of three phases—elimination, equilibrium, and escape (Figure 4).¹ Both innate and adaptive immunity belong to the elimination phase, also referred to as immunosurveillance. If the immune system is unable to completely eradicate the tumor cells, the microenvironment enters the next phase, equilibrium. This may be a prolonged period of time during which tumor cells are maintained in a state of functional dormancy by the immune system. However, a byproduct of this selective pressure is the emergence and promotion of tumor cell variants with decreased immunogenicity, thereby increasing resistance to immunologic attack. Following this phase, tumor cell variants with low immunogenicity can enter the escape phase, during which the immunologically sculpted tumor successfully evades the immune system and grows sufficiently to be clinically detected.

In this favorable immunoediting environment, tumors can progress where the antitumor adaptive and innate response are blocked. Several immune protumor effector mechanisms are upregulated by chronic inflammation, leading to the hypothesis that inflammation promotes carcinogenesis and tumor growth by altering the balance between protumor and antitumor immunity. In this scenario, the immune system plays dual roles with host-protective and a tumor-promoting activities.

Immune checkpoints refer inhibitory pathways in the immune system that are crucial for maintaining normal self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues, in order to minimize collateral tissue damage.⁴ Certain immune checkpoints can be exploited by tumors as immune resistance mechanisms.

Two of the most investigated checkpoint receptors in terms of immunotherapeutic targets for NSCLC are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) receptor, which downregulate T-cell activation, proliferation, and function through different mechanisms.^5,6

CTLA-4 is expressed on the surface of T cells after activation and competes with the co-stimulatory T-cell CD28 receptor for CD80/86 expressed by antigen-presenting cells (APCs), providing an inhibitory signal to the T cell (Figure 5).¹

Large numbers of T_reg cells that constitutively express high levels of CTLA-4 on their surface and directly inhibit T-cell proliferation have been found in NSCLC tumors.^7,8

Tumors can develop immune resistance via the PD-1 pathway.¹ Upregulation of the PD-1 receptor on activated T cells and subsequent binding to one of its ligands, programmed death ligand-1 (PD-L1) or PD-L2, provide an inhibitory signal during the effector phase of the T-cell response, reducing cytokine production, cell proliferation, and cell survival signaling. PD-1 is also expressed at high levels on T_reg cells, enhancing their proliferation in the presence of a PD-1 ligand. In addition, PD-1 may be induced on activated NK cells, thereby limiting their lytic activity. PD-L1 and PD-L2 are also usually expressed on tumor cells. Tumor-infiltrating CD8+ T cells have shown increased PD-1 expression that was associated with impaired immune function in NSCLC.⁹ In addition, PD-L1 expression has also been found to be upregulated on NSCLC tumor cells.¹⁰

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