Mechanisms of Immune Escape in Tumors
Although the human immune system uses powerful immune cells and various immune measures, some immunogenic tumors evade clearance after initially being attacked by the immune system, which is known as immune escape.
The most common strategy for immune escape is to stop expressing tumor-associated antigens (TAA) or tumor-specific antigens (TSA) that have attracted the attention of the immune system and its cytotoxic lymphocytes. The tumor cells inhibit the expression of these antigens without damaging their own survival and proliferation. The tumor cell population often suppresses the expression of genes encoding antigen by promoter methylation and hides the mutated part among them. Cells in which antigen expression is absent can evade immune attacks and ultimately become the major cells in tumor tissue.
In tumors where the expression of certain TAA or TSA is essential for tumor growth, tumor cells need to adopt other strategies to evade immune system killing. One key and commonly used immune escape strategy is down-regulating the expression of MHC class I molecules that present tumor antigens. Loss of MHC class I molecule expression is often associated with tumor cell invasiveness and metastasis.
In addition, immune cells also have a series of immune checkpoint proteins that help maintain immune tolerance by regulating the intensity of their own immune response. Tumor cells often up-regulate immune checkpoint signal molecules to inhibit immune cells and provide the opportunity for tumor cell growth and escape.
Tumor Immune Cycle
The tumor immune cycle summarizes scientific knowledge of every step in the effective anti-tumor immune response. The cycle begins when the tumor antigen is recognized by the immune system.
Cancer has genomic instability and mutations. Regardless of their tissue of origin, all cancers have genetic changes that can produce proteins expressed differently from normal cells, namely tumor antigens. Secondly, some cancers express non-mutation-related tumor antigens, such as proteins expressed at immunologically privileged sites, viral proteins, or proteins encoded by endogenous retroviral genes.
When these antigens are absorbed and processed by antigen-presenting cells (APCs), APCs migrate to secondary lymphoid organs and activate naive T cells with a series of highly coordinated co-stimulatory signals, such as those mediated by the CD28/B7-1/2 pathway. To maintain balance and prevent excessive responses to non-self-antigens, the immune system also develops a highly coordinated negative feedback loop. CTLA-4 is one of the main negative regulatory factors for T cell-mediated immune responses.
Once activated, effector T cells systemically infiltrate tumor lesions, recognize cancer cells presenting tumor antigens by the major histocompatibility complex (MHC), and kill target cancer cells. In turn, cancer cells release new antigens presented by APCs, identifying and attacking the tumor through the initiation and activation of more T cells, further amplifying the anti-tumor immune response.
The last stage of the tumor immune response is usually regulated by a complex network of stimuli and inhibitions. The PD-1/PD-L1 pathway is one of the main inhibitory pathways. TCR binding to its homologous antigen-MHC complex, coupled with cytokine stimulation such as IL-2 stimulation, can induce PD-1 expression. PD-1’s binding to PD-L1 on target cells inhibits T cell proliferation and IL-2 production, inhibiting immune response. Therefore, reasonable combination immunotherapy must aim to coordinate the promotion of T cell activation and effector function and simultaneously coordinate the inhibition of the mechanisms that suppress T cells.
Tumor Immune Microenvironment
Studying tumor immunity based on the immune microenvironment (TME) classification system can serve as the first step in evaluating cancer immunotherapy and determining potential tumor resistance mechanisms. The immune microenvironment classification is based on two main factors: (1) PD-L1 tumor expression; (2) immune cell infiltration, mainly tumor-infiltrating lymphocytes (TIL). Accordingly, four different temporal subtypes can be described: T1 (PD-L1-, TIL-), T2 (PD-L1+, TIL+), T3 (PD-L1-, TIL+), and T4 (PD-L1+, TIL-).
In tumors without immune cell infiltration (T1 or T4), there is no anti-cancer immunity at the cancer site, indicating defects in tumor antigen release, presentation, initiation, and activation of immune cells, or the transfer of immune cells to the cancer site.
In tumors with immune cell infiltration (T2 and T3), there is an anti-tumor immune response. However, the immune suppression microenvironment can inhibit the killing activity of effector immune cells against cancer cells. The lack of PD-L1 in T3 (PD-L1-, TIL+) suggests that tumor immunity suppression is mainly mediated by mechanisms other than the PD1/PD-L1 pathway.
On the other hand, although TIL appears in T2 and T3 periods, its location and function are critical. The immune-inflammatory phenotype of T lymphocytes is often accompanied by myeloid cells and monocytes, and TIL infiltrating into the tumor site, whereas the immune-rejection phenotype is characterized by immune cells lingering in the matrix around tumor cells but not penetrating the tumor.
Nowadays, people increasingly realize that many cancer patients have anti-tumor T cells, but the microenvironment can effectively suppress their immune response. Therefore, what is essential is not to enhance the immune system but to restore the immune microenvironment. In particular, targets for normalizing the immune microenvironment in T1 (PD-L1-, TIL-) are still to be discovered and validated. Looking for and defining such targets from T1 tumors is expected to be the next game-changer in tumor immunotherapy.
Immune checkpoint inhibitors
In 1987, scientists discovered that an immunoglobulin present on the surface of CD4+ or CD8+ T cells, known as cytotoxic T-lymphocyte antigen-4 (CTLA-4), paving the way for the discovery of all checkpoint inhibitors in the future.
After the discovery of CTLA-4, Ishida et al. found programmed death receptor-1 and programmed death ligand-1 (PD-1/PD-L1) in 1992. PD-1/PD-L1 inhibitors are now the cornerstone of cancer immunotherapy. There are multiple PD-1 inhibitors on the market, including nivolumab, pembrolizumab, and cemiplimab, as well as PD-L1 inhibitors such as atezolizumab, avelumab, and durvalumab. Currently, over 2,000 PD-1/PD-L1 inhibitor combination trials for various malignant tumors are underway.
However, only 10-30% of patients show long-term, sustained responses to PD-1 treatment, and most of the population lacks a response. The development of acquired resistance and immune-related adverse events (IRAEs) is also a significant obstacle. One way to overcome PD-1 treatment limitations is to target other immune checkpoints associated with the tumor microenvironment, such as LAG-3, TIGIT, TIM-3, VISTA, B7-H3, ICOS, and BTLA. These new immune checkpoints are feasible and promising options for treating solid tumors, and multiple clinical trials are actively researching them.
In addition, combination therapy with checkpoint inhibitors, such as the simultaneous blockade of CTLA-4 and PD-1, can suppress tumor development through different mechanisms. So far, the FDA has approved the combination of ipilimumab and nivolumab to treat various malignant tumors. However, increased toxicity remains a barrier for many combination therapies.
Reference
1.The Biology of Cancer, 2nd edition. Robert A. Weinberg