Emerging Immunotherapy Targets in Lung Cancer
Lung cancer remains the leading cause of cancer-related mortality globally, despite advancements in conventional therapies such as surgery, chemotherapy, radiotherapy, and targeted therapies. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized treatment paradigms by leveraging the host immune system to achieve durable responses. While inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) axis have demonstrated clinical benefits, only 15–25% of non-small cell lung cancer (NSCLC) patients respond to these therapies. Resistance mechanisms and the immunosuppressive tumor microenvironment (TME) necessitate the exploration of novel immune checkpoints. This review highlights emerging targets beyond PD-1/PD-L1 and CTLA-4, focusing on co-inhibitory and co-stimulatory pathways in T cells, macrophages, and natural killer (NK) cells.
Co-Inhibitory T Lymphocyte Checkpoints
Lymphocyte Activation Gene-3 (LAG-3)
LAG-3 (CD223), located on chromosome 12, shares structural homology with CD4 and binds major histocompatibility complex (MHC) class II with high affinity. It is expressed on activated NK cells, T cells, dendritic cells (DCs), and regulatory T cells (Tregs). LAG-3 suppresses CD4+ T cell metabolism and mitochondrial biogenesis, while fibrinogen-like protein 1 (FGL1), a novel LAG-3 ligand secreted by tumor cells, independently inhibits T cell activation.
In NSCLC, LAG-3 expression correlates with PD-1/PD-L1 levels and poor prognosis, though conflicting studies associate LAG-3+ tumor-infiltrating lymphocytes (TILs) with improved survival. Preclinical studies demonstrate that anti-LAG-3 antibodies (e.g., LBL-007) synergize with PD-1 inhibitors to enhance tumor control. Clinical trials evaluating combinations of LAG-3-targeting agents (e.g., IMP321, LAG525) with anti-PD-1 therapies (NCT03625323, NCT03365791) are ongoing for NSCLC and small cell lung cancer (SCLC).
T-cell Immunoglobulin and Mucin-Domain-Containing Molecule 3 (TIM-3)
TIM-3, expressed on Th1 cells, cytotoxic T lymphocytes (CTLs), Tregs, and NK cells, interacts with galectin-9 (Gal-9) to induce Th1 cell death and promote Treg-mediated immunosuppression. In NSCLC, TIM-3 overexpression on CD4+ T cells and NK cells correlates with advanced tumor stage, lymph node metastasis, and poor survival. Exosomal TIM-3 and Gal-9 levels in peripheral blood serve as non-invasive biomarkers for prognosis.
TIM-3 blockade reverses T cell exhaustion and synergizes with PD-1 inhibitors. Phase I trials of TIM-3-targeting agents (TSR-022, RO7121661) in combination with PD-1 inhibitors or chemotherapy are underway (NCT03307785, NCT03708328).
B7 Homolog 3 (B7-H3)
B7-H3 (CD276) exhibits dual roles: it co-stimulates T cells in early studies but suppresses IL-2 and IFN-γ production in later findings. Overexpressed in 70–80% of NSCLC cases, B7-H3 associates with smoking history, poor prognosis, and resistance to PD-1 inhibitors. Preclinically, dual blockade of B7-H3 and PD-1 enhances CD8+ T cell infiltration and cisplatin sensitivity. Enoblituzumab (MGA271), a B7-H3 monoclonal antibody (mAb), is being tested in combination with PD-1/CTLA-4 inhibitors (NCT02381314, NCT02475213).
V-Domain Immunoglobulin Suppressor of T Cell Activation (VISTA)
VISTA, a B7 family member with homology to PD-L1, inhibits T cells via PSGL-1 binding in acidic TME and stabilizes Tregs. In NSCLC, stromal VISTA expression correlates with CD8+ T cell infiltration and longer survival, while tumor cell VISTA predicts poor outcomes. Post-anti-PD-1 therapy VISTA upregulation suggests its role in resistance. Therapeutic strategies targeting VISTA remain in preclinical stages.
T-cell Immunoglobulin and ITIM Domain (TIGIT)
TIGIT and CD96 compete with CD226 for CD155 binding, suppressing NK and T cell function. In NSCLC, TIGIT is expressed on 58% of CD8+ TILs and synergizes with PD-1 to induce T cell exhaustion. Anti-TIGIT mAbs (MTIG7192A, tiragolumab) combined with PD-L1 inhibitors (atezolizumab) are in phase II/III trials (NCT03563716, NCT04294810).
Co-Stimulatory T Lymphocyte Checkpoints
Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 (HHLA2)
HHLA2, a B7 family member exclusive to primates, binds CD28 homolog (CD28H/TMIGD2) to co-stimulate T cells or inhibit them in the presence of TCR signaling. Overexpressed in 65% of NSCLC cases, HHLA2 is prevalent in PD-L1-negative tumors and correlates with EGFR mutations. Its prognostic significance remains unclear, necessitating further mechanistic studies.
Glucocorticoid-Induced TNFR-Related Receptor (GITR)
GITR activation promotes effector T cell function and depletes Tregs. In SCLC, GITR ligand (GITRL) induces apoptosis, while GITR agonists combined with PD-1 inhibitors and radiation improve survival in preclinical models. Phase I/II trials of GITR mAbs (BMS-986156) with PD-1/CTLA-4 inhibitors are ongoing (NCT04021043).
CD27
CD27 agonists (varlilumab) stimulate effector T cells and reduce Tregs, but chronic signaling causes exhaustion. High soluble CD27 levels predict poor NSCLC prognosis. Trials combining CD27 mAbs with PD-L1 inhibitors and radiation are in progress (NCT04081688).
Co-Inhibitory Macrophage Checkpoints
CD47/Signal Regulatory Protein α (SIRPα)
The CD47-SIRPα axis, a “don’t eat me” signal, inhibits macrophage phagocytosis. CD47 is overexpressed in NSCLC and SCLC, correlating with metastasis and poor survival. CD47 blockade (e.g., TTI-621, magrolimab) enhances macrophage-mediated tumor cell clearance and synergizes with autophagy inhibition. Clinical trials are evaluating CD47-targeting agents in lung cancer.
Indoleamine 2,3-Dioxygenase 1 (IDO1)
IDO1 metabolizes tryptophan to kynurenine, suppressing T cells and promoting Tregs. In NSCLC, IDO1/PD-L1 co-expression predicts poor prognosis, while high tryptophan/kynurenine ratios correlate with anti-PD-1 resistance. IDO1 inhibitors (epacadostat, indoximod) combined with PD-1 inhibitors are in phase II trials (NCT03322540, NCT03322566).
Co-Inhibitory NK Cell Checkpoints
Inhibitory killer immunoglobulin-like receptors (KIRs) and CD96 suppress NK cell cytotoxicity. In NSCLC, KIR2D and KIR3DL1 overexpression correlates with poor outcomes. CD96 blockade reduces metastases via NK cell activation in preclinical models. Clinical trials targeting NK checkpoints are nascent but promising.
Conclusions
The immunosuppressive TME in lung cancer necessitates a multifaceted approach to immunotherapy. Emerging targets such as LAG-3, TIM-3, B7-H3, VISTA, TIGIT, and CD47/SIRPα offer novel avenues to enhance effector T cell function, deplete Tregs, and activate innate immunity. Combination strategies with PD-1/CTLA-4 inhibitors, chemotherapy, or radiation hold potential to overcome resistance. Clinical trials must address biomarker-driven patient stratification and therapeutic sequencing to optimize outcomes.
doi.org/10.1097/CM9.0000000000001082
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