Cancer immunoediting represents a fundamental process governing the complex relationship between the immune system and developing tumors, progressing through three critical phases that determine whether cancer cells are eliminated or allowed to flourish. Recent research has illuminated how tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) serve as key orchestrators of this process, with their functional states determining tumor fate.
The Three Phases of Cancer Immunoediting
The cancer immunoediting theory, established through mouse tumor model studies, describes how the immune system simultaneously protects against and shapes tumor development. This process unfolds in three sequential phases: elimination, equilibrium, and escape, each characterized by distinct immune cell behaviors and tumor responses.
During the elimination phase, the immune system functions as intended, with various anti-tumor immune subsets working to destroy cancer cells. CD8+ cytotoxic T lymphocytes lead this response by recognizing tumor antigens presented on MHC-I molecules and triggering apoptosis through death receptor ligation, FASL, TRAIL, and the release of granzyme B and perforin. Natural killer cells complement this response by inducing apoptosis through cytolytic granules containing granzymes and perforins, while also expressing activating receptors like NKG2D and DNAM-1.
M1-polarized macrophages contribute significantly to tumor elimination through both direct and indirect mechanisms. They directly mediate cytotoxicity by generating reactive oxygen species (ROS) and nitric oxide (NO), which have cytotoxic effects on tumor cells. Indirectly, M1 macrophages secrete large amounts of pro-inflammatory cytokines IFN-γ and IL-12, which enhance NK cell and cytotoxic T cell infiltration and activation at tumor sites.
The equilibrium phase represents the longest stage of cancer immunoediting, potentially lasting years. During this phase, immune selection pressure continuously removes tumor cells while promoting the survival of resistant variants. This Darwinian selection process destroys many original tumor variants while allowing those with distinct mutations that boost resistance to immune attack to survive and proliferate.
Research has shown that adaptive immunity components—CD4+ T cells, CD8+ T cells, IL-12, and IFN-γ—are responsible for maintaining tumor cells in equilibrium by exerting immune selection pressure. The balance between effector and regulatory immune cells becomes the most critical factor during this phase, with the ratio of elimination-promoting IL-12 to persistence-promoting IL-23 determining whether tumors remain controlled.
The Escape Phase and Immune Suppression
The escape phase marks the transition from immune control to tumor progression, characterized by the infiltration of tumor-promoting immune cells that suppress anti-tumor responses. Regulatory T cells (Tregs), characterized by FOXP3 and CD25 expression, infiltrate the tumor microenvironment through multiple mechanisms and facilitate tumor growth through various suppressive functions.
Tregs secrete immunosuppressive cytokines including TGF-β, IL-10, and IL-35, which directly inhibit effector T cell responses. They can restrict antigen-presenting cell activity by downregulating CD80 and CD86 expression in a CTLA-4-dependent manner, preventing tumor antigen presentation and activation of tumor-specific T cells. Additionally, Tregs deplete available IL-2 through IL-2/IL-2-receptor signaling, further suppressing CD4+ and CD8+ T cell proliferation and functionality.
M2-polarized TAMs represent another critical component of the immunosuppressive escape phase. These macrophages secrete various growth factors including platelet-derived growth factor (PDGF), TGF-β1, hepatocyte growth factor (HGF), and epidermal growth factor (EGF) family members that facilitate tumor cell proliferation and survival. M2 macrophages also enhance tumor migration by secreting matrix metalloproteinases (MMPs), cathepsins, and serine proteases that degrade the extracellular matrix and facilitate neo-angiogenesis.
The immunosuppressive cytokine IL-10, produced by M2 TAMs, inhibits the cytotoxic activity of Th1 cells, NK cells, and CD8+ T cells against tumor cells. Furthermore, TAM-derived CCL17/CCL22 significantly enhances Treg recruitment to the tumor microenvironment through the chemokine receptor CCR4, creating a self-reinforcing cycle of immunosuppression.
Therapeutic Targeting of TILs and TAMs
Understanding the dual roles of TILs and TAMs in cancer immunoediting has led to innovative therapeutic approaches. TIL therapy represents a novel adoptive cell therapy approach that harnesses patients' own immune systems to fight cancer. In February 2024, the FDA approved Lifileucel, an autologous TIL-based therapy, marking a significant milestone in this field.
Advanced TIL therapies are incorporating genetic engineering approaches to enhance efficacy. IOV-4001, a genetically engineered PD-1 knockout TIL created using CRISPR-Cas9 gene editing, is being investigated in Phase I/II trials for advanced non-small-cell lung cancer and metastatic melanoma. These modifications aim to overcome the immunosuppressive signals that typically limit TIL function within the tumor microenvironment.
Targeting immune checkpoint pathways has shown promise in restoring immune function. The combination of anti-LAG-3 and anti-PD-1 monoclonal antibodies enhances IFN-γ production and T cell cytotoxicity, leading to more effective tumor growth inhibition. Similarly, simultaneous inhibition of TIM-3 and PD-1 has been shown to reinstate effector T cell functionality and amplify anti-tumor immune responses.
Macrophage Repolarization Strategies
Therapeutic approaches targeting TAMs focus on reprogramming M2-type macrophages into the pro-inflammatory, anti-tumor M1 subtype. TLR agonists like imiquimod and 852A have shown notable anticancer effects in preclinical studies by promoting M1 polarization. The TLR9 agonist lefitolimod has been evaluated in multiple clinical trials, where it promotes M1 polarization and enhances anti-tumor immune responses.
Targeting the CSF-1/CSF-1R pathway represents another promising approach, as this signaling axis plays a critical role in TAM recruitment and survival. Studies have shown that specific targeting of CSF-1R significantly inhibits tumor growth by depleting M2-type macrophages. The CSF-1-targeting monoclonal antibody lacnotuzumab, when combined with chemotherapy, led to better outcomes compared to chemotherapy alone in patients with advanced triple-negative breast cancer.
Future Directions and Challenges
The complexity of cancer immunoediting presents both opportunities and challenges for therapeutic intervention. Biomarkers associated with TILs and TAMs serve as important predictors of treatment response, with high density of CD8+ T cells consistently linked to improved clinical outcomes across multiple cancer types. The ratio of M1 to M2 macrophages within tumors has been correlated with both patient survival and response to immunotherapy.
However, tumor heterogeneity and the dynamic nature of the tumor microenvironment continue to pose significant challenges. The heterogeneity of immune cell populations within the tumor microenvironment significantly influences immunotherapy effectiveness and cancer progression. Understanding these nuances remains essential for tailoring personalized treatment strategies and improving clinical outcomes.
Emerging therapeutic strategies increasingly focus on simultaneously targeting both TILs and TAMs to reshape the tumor immune microenvironment. Approaches such as PI3K-γ pathway inhibition lead to TAM repolarization with increased IL-12 and IFN-γ production, alongside greater recruitment and maturation of CD8+ T cells within tumors. These combination strategies represent the future of cancer immunotherapy, offering the potential to overcome the complex immune evasion mechanisms that tumors employ during the escape phase of immunoediting.
