The Immune System in Cancer: Its Roles and How We Can Harness It

The immune system is designed to recognize and eliminate cancer cells, but tumors have developed sophisticated strategies to evade immune detection and use immune cells to support their growth and metastasis.

Immunotherapy approaches aim to reinvigorate the immune system against tumors, restoring its cancer-killing abilities to fight cancer more effectively.

This article explores the relationship between the immune system and cancer and outlines therapeutic strategies that leverage a patient’s immune system to treat cancer.

The role of the immune system in cancer

Tumor development

As tumors develop, cytotoxic immune cells like natural killer (NK) and CD8+ T cells target and destroy immunogenic cancer cells (those visible to the immune system).

NK cells exert an anti-tumor effect in response to changes in cancer cell surface molecule expression that would either deinhibit or directly activate cytotoxic NK cell function. This may occur as a consequence of aberrant cell proliferation, DNA damage or Ras-pathway activation.

Antigen-presenting cells cause CD8+ cells to transform into cytotoxic T lymphocytes, which can directly destroy cancer cells. CD4+ T helper 1 cells also secrete proinflammatory cytokines to promote T-cell priming and activation as well as the anti-tumoral activity of NK cells and macrophages.

The non-immunogenic cancer cells can continue to grow and spread.

Early in tumor growth, cancer cells stimulate changes in the host tissues to support tumor progression, shaping the tumor microenvironment (TME). Immune cells can infiltrate the TME, and the presence of cytotoxic T cells and T helper 1 cells is associated with positive prognoses in most cancer patients.

The landscape of immune cells in the TME can be classified into three main types. Immune infiltrated TMEs have immune cells distributed throughout, indicating an active immune response. Immune excluded tumors have T cells at the periphery that have not penetrated the TME, and immune silent tumors completely lack infiltrating immune cells.

Tumor growth and cancer progression

As cancers grow, the TME has the inherent ability to convert tumor-associated macrophages (TAMs) from a proinflammatory state to an anti-inflammatory state, supporting tumor progression. Pro-tumor TAMs secrete cytokines that induce immunosuppression, enabling the tumor to avoid detection by the immune system. They also stimulate angiogenesis and lymphogenesis and promote epithelial-mesenchymal transition and metastasis, further supporting cancer growth and spread. Pro-tumor TAMs have also been noted to induce suppression of anti-tumor effector immune cells.

Similar to TAMs, neutrophils are also proposed to exist in pro- and anti-tumor states. Pro-tumor neutrophils are thought to contribute to inflammation during tumor initiation and progression, and promote tumor cell invasion, angiogenesis and cancer cell proliferation by secreting neutrophil elastase at inflammation sites.

Alongside pro-tumor immune cells, other immune cells also work to fight and destroy cancer cells. T cells are one of the most prominent immune cells found in the TME, and they can infiltrate the core of a tumor.

T-cell activity is dependent on cancer cells expressing antigens in the context of MHC on their cell surface. As a tumor grows and the TME changes, different antigens are presented on the surface of cancer cells, altering how T cells can respond to the tumor.

Regulatory T cells within the TME, which ordinarily suppress inflammatory responses and prevent autoimmunity, dampen anti-tumor immune responses by cytotoxic T cells and NK cells and can directly nurture tumor growth by secreting growth factors.

Metastasis

TAMs promote metastasis by triggering extracellular matrix remodeling alongside enhancing tumor cell mobility and invasiveness, accelerating dissemination of tumor cells away from the primary site.

Some cancers establish a pre-metastatic niche before tumor cells move from the primary site by secreting factors that recruit immature myeloid cells – like monocytes, macrophages and mast cells – to the metastatic site.

Neutrophils have also been identified as pioneer cells within the pre-metastatic niche, supporting the survival and proliferation of disseminated cells.

When tumor cells reach the metastatic site, a subset of TAMs can promote their extravasation and growth at the secondary site.

In contrast, “patrolling” monocytes found in the lungs have been noted to interact with metastasizing cancer cells, promoting NK cell recruitment and activation to reduce tumor metastasis.

How can we exploit the immune system for cancer treatment?

Adoptive T-cell transfer

Adoptive T-cell therapy involves culturing and modifying a patient’s immune cells to improve their capacity for tumor killing, then reinfusing them into the patient. While chimeric antigen receptor (CAR) T-cell therapy is perhaps the most well-known type of adoptive cell therapy, gene-modified T cells that express a transgenic T-cell receptor and tumor-infiltrating lymphocytes also offer promising avenues for cancer treatment.

“All cellular immunotherapies currently approved for clinical use employ T cells as main effectors of their action,” said Prof. Sebastian Kobold, professor and deputy director of clinical pharmacology at LMU Klinikum.

“The concept [of CAR T-cell therapy] leverages natural functions of T cells, which is their ability to kill a specific cell when properly activated,” Kobold explained. “Chimeric antigen receptors emerged over 30 years ago as a strategy to capitalize on T-cell function while overcoming major histocompatibility complex restrictions”.

Thus far, cellular therapies have seen success in treating blood cancers, but the heterogeneous antigen expression and hostile TME in solid tumors have hindered development.

However, “results from early phase clinical studies indicate that CAR T cells may be efficacious in certain distinct solid cancer entities, when aiming at certain antigens”, reports Kobold.

Optimizing the design of CAR T cells, gating their activity or combining cell therapy with other modalities could offer promise for enhancing the efficiency of CAR T-cell therapy for solid tumors.

For Kobold, a particular interest in the lab “has been in modular CAR formats, where CAR activity may become conditional. Our approach was to use mono-or polyspecific antibodies to capitalize on molecular biology and recombinant technologies.”

Checkpoint inhibitors

To establish immune system tolerance, cancer cells can express immune checkpoint molecules on their cell surface, downregulating immune responses by inhibiting the normal activation of T cells.

Immune checkpoint inhibitors are designed to bind to the immune checkpoint molecule on cancer cells or T cells alike, blocking the connection between the receptor and its ligand on immune cells and restoring immune cell function.

Many tumor types overexpress ligands (PD-L1 and PD-L2) for the inhibitory immune checkpoint molecule programmed death 1 (PD-1), causing T cells to bind to the cancer cell and resulting in T-cell inactivation or exhaustion.

Several PD1 and PD-L1 inhibitors have been developed to block the PD-1/ PD-L1 pathway and reinvigorate T cells. Many PD-L1 inhibitors have been approved by the US Food and Drug Administration (FDA) and have shown high survival rates and remission in patients with melanoma and non-small cell lung cancer, becoming some of the most frequently prescribed anticancer therapies.

Similarly, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) ligands CD80 and CD86 on tumor cells and antigen-presenting cells can bind to CTLA-4 to decrease T-cell activation. Anti-CTLA-4 monoclonal antibodies like ipilimumab can prevent this binding interaction and revitalize the T cells, driving an anti-tumor immune response.

However, tumors are prone to developing resistance to immune checkpoint inhibitors, leading to reduced response, and patients can experience immune-related adverse effects that complicate treatment.

Immune checkpoint inhibitors have the potential to be combined with other therapeutic modalities to improve patient outcomes by targeting multiple biological pathways simultaneously.

Cancer vaccines

“The principle behind [cancer vaccines] is straightforward: instead of targeting viral proteins (as in COVID-19 vaccines), we can design cancer-specific mRNA vaccines to stimulate an immune response against tumor-associated antigens (TAAs) or neoantigens,” said Prof. Siow-Ming Lee, a professor of medical oncology at University College London. “Both approaches are being explored, as TAAs are commonly expressed in tumors, while neoantigens are unique to each patient’s cancer. The hope is that by combining mRNA vaccines with checkpoint inhibitors, we can further enhance immune responses against the tumor.”

Lee and his colleagues recently treated the first lung cancer patient with an mRNA vaccine in a clinical trial. The patient received six different vaccine types targeting different cancer proteins alongside immunotherapy and has thus far shown a partial response.

“This is still a phase 1 trial, primarily assessing safety and dose escalation, but if promising, we will expand into phase 2 and eventually phase 3 trials with larger patient cohorts,” noted Lee.

“We now have a better understanding of the common side effects of mRNA-based therapies, such as transient fever with immune activation, and can track T-cell clones to see if they are effectively targeting cancer proteins. Genomic sequencing (NGS) allows us to identify potential neoantigens, while immune monitoring techniques such as T-cell receptor (TCR) sequencing and ELISpot assays have made it easier to study these responses in vivo, helping us track whether a patient is mounting an effective immune response,” he added.

Cancer vaccines may also help prevent recurrence after surgery by generating long-term immune memory against residual tumor cells.

The biggest challenge facing cancer vaccines, according to Lee, is “identifying reliable biomarkers that predict patient response and developing strategies to stimulate immunity in those who don’t naturally respond. Advances in single-cell analysis and spatial profiling of the TME may provide deeper insights into these mechanisms.”

Antibody therapy

Bispecific antibodies are another promising avenue to therapeutically exploit the immune system to treat cancer. Bispecific T-cell engaging antibodies (TCE) are a subset of bispecific antibodies that usually target an immune-related molecule and a tumor antigen at the same time, redirecting and activating the T cells to specific tumor antigens. The T cells can then release perforin and other granzymes to lyze the tumor cells.

TCEs have been approved by the FDA to treat patients with certain blood cancers and a particular subtype of melanoma, but they come with the risk of cytokine release syndrome and neurological adverse effects.

Tumors can also “escape” the activity of TCEs through immune suppression or loss of the target antigen, but combining TCEs with PD-1/PD-L1 inhibitors and understanding the mechanisms of antigen loss could help to improve their efficacy.

Recent breakthroughs in immunotherapy have revolutionized cancer treatment, offering new hope to patients. As research advances, a deeper understanding of the interactions between the immune system and cancer cells will help to develop more effective therapies and combination therapy approaches for cancer.