Tumor immune microenvironment characterization and response to anti-PD-1 therapy

In recent years, further understanding of the interaction between the immune system and tumor growth has led to the development of several immunotherapies. These immunotherapies include cancer vaccines and immune checkpoint inhibitors that have been tested in various solid tumors, including those traditionally considered non-immunogenic, such as non-small cell lung cancer (NSCLC). In physiological state, T-cell-mediated immune response against foreign antigens is regulated by stimulatory and inhibitory signals, which are critical to prevent autoimmunity and protect normal tissues after immune system activation. Cancer cells harbor different genetic and epigenetic alterations; thus, neoantigens that are potentially recognized and eliminated by the immune system are expressed. Adaptive immune responses, particularly IFN-γ-secreting T cells, exert a core function in tumor immune surveillance. However, tumors can escape this surveillance and maintain an immunosuppressive microenvironment through multiple mechanisms, including recruitment of regulatory cells (e.g., regulatory T cells, myeloid-derived suppression cells, and type 2 macrophages) and production of molecules suppressing antitumor T-cell responses (e.g., interleukin-10 and transforming growth factor-β). Tumor growth is also associated with immunomodulation of T-cell response through enhancement of co-inhibitory molecules or immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed cell death-1 (PD-1), on T cells 1,2. Immunotherapies may affect various tumors by activating adaptive immune system response, including blockade of immune checkpoint pathways. PD-1 receptor is highly expressed by activated T cells, B cells, and natural killer cells 3. The well-known ligands of PD-1 are PD-L1 (or B7-H1) and PD-L2 (or B7-DC). PD-L1 is expressed in macrophages and can be induced by inflammatory cytokines on tumors, immune cells, and various tissues (Figure 1). After ligand binding, PD-1 inhibits kinase signaling pathways involved in T-cell activation; thus, this process prevents overstimulation of immune response. PD-L1 also binds CD80 receptor, which is another negative regulator of T-lymphocyte activation. PD-1 primarily inhibits T-cell activity in the effector phase within tissues and tumors, whereas CTLA-4 regulates immune responses early in T-cell activation. Therefore, PD-L1/PD-1 axis blockade should enhance anticancer immunity. Antibodies directed against CTL A-4 and PD-1/PD-L1 pathway have been demonstrated to be effective treatment strategies, which induce durable tumor responses in patients with various malignancies 4. Several anti-PD1 antibodies, including nivolumab (BMS-936558), have been developed and are currently in advanced phases of clinical development; nivolumab is a full human IgG4 monoclonal antibody that binds to PD-1 receptor and can block interaction with both of its ligands. Nivolumab disrupts negative signaling triggered by PD-L1/PD-L2 …