The field of immuno-oncology focuses on the immune system’s role in recognizing, targeting, and eliminating cancer cells. Tumor-specific immune responses offer a pathway for precisely targeting cancer cells while sparing healthy tissue, potentially providing long-term protection against recurrence through immune memory. The theory of immunosurveillance—the immune system’s capacity to detect and destroy emerging cancer cells—has guided much of modern immuno-oncology research, with efforts aimed at enhancing the immune system’s natural ability to identify and eradicate tumors.1
Immunosurveillance and Tumor Antigens
Tumor specificity in immune responses relies on tumor-associated antigens (TAAs)—molecules unique to or abnormally expressed in cancer cells. These antigens arise from viral infections, genetic mutations, or altered protein expressions and serve as immune system targets. Natural killer (NK) cells and cytotoxic T cells are critical players in immunosurveillance. NK cells detect and destroy cells with abnormal antigens, while macrophages and dendritic cells process the destroyed tumor cells and present their antigens to T and B cells, activating the adaptive immune response.
Despite the immune system's effectiveness in some individuals, many cancers manage to evade immunosurveillance, progressing through phases of elimination, equilibrium, and ultimately escape. During escape, tumors can suppress immune responses through mechanisms like antigen loss, HLA downregulation, and resistance to immune cell killing.
Related: The Role and Development of TCR-like Antibodies in Cancer Immunotherapy
Tumor Immune Evasion and the Tumor Microenvironment
Tumors exploit the tumor microenvironment (TME) to suppress immune function and evade destruction. The TME consists of cancer cells and various supportive immune cells that enable tumor growth and suppress immune activation. Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are prominent in the TME and release immunosuppressive cytokines that inhibit cytotoxic immune responses. Additionally, tumor cells can attract pro-inflammatory cells, fostering chronic inflammation that paradoxically supports tumor growth rather than elimination.
These insights into immune evasion highlight the need for immunotherapies that can overcome immune suppression within the TME, aiming to convert it from an immune-suppressive to an immune-supportive environment.
Advances in Immunotherapy: Active and Passive Approaches
Immunotherapies generally fall into active or passive categories. Passive Immunotherapies provide preformed immune components such as monoclonal antibodies or cytokines that directly target cancer cells. Monoclonal antibodies like trastuzumab and rituximab bind to specific cancer antigens, flagging cancer cells for immune destruction or delivering cytotoxic payloads. Although effective, these treatments are often administered later in disease progression when immune function is compromised, limiting their impact.
Meanwhile, active Immunotherapies aim to stimulate the patient’s own immune response against cancer cells. Cancer vaccines deliver tumor antigens to prompt an immune response, while checkpoint inhibitors—like anti-CTLA-4 and anti-PD-1 antibodies—remove inhibitory signals that prevent T cells from attacking cancer cells.
Checkpoint inhibitors in particular have achieved success in treating advanced cancers by blocking inhibitory pathways, such as PD-1/PD-L1 interactions, that allow tumors to evade immune detection. By releasing these checkpoints, T cells can remain active and target cancer cells, increasing the chances of achieving a durable immune response.
Related: Immune Checkpoint Inhibitors and Antibody Therapeutics: A Paradigm Shift in Cancer Treatment
Combination Immunotherapy and Tumor Microenvironment Modulation
Recognizing that single immunotherapies may be insufficient for advanced cancers, there is a growing interest in combination therapies. Combining immunotherapy with traditional treatments like chemotherapy or radiation, or with other immune-targeting agents, can amplify antitumor effects. Ipilimumab, for example, an anti-CTLA-4 antibody, enhances T-cell activation and proliferation, while PD-1 inhibitors sustain cytotoxic T-cell responses within the TME. This multi-target approach counters the adaptive mechanisms tumors develop to resist single-agent therapies.
Research also suggests that combining immunotherapies targeting immune suppression within the TME—like inhibitors of Tregs or MDSCs—with tumor-targeting antibodies can create a more favorable immune environment. The goal is to shift the TME from promoting immune evasion to supporting tumor rejection.
Finn, O. J. (2012). Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology, 23, viii6–viii9. https://doi.org/10.1093/annonc/mds256
Antibody specificity refers to an antibody's ability to selectively bind to a unique epitope on a target antigen while avoiding interactions with unrelated antigens. This property arises from the highly specialized antigen-binding site located in the variable region of the antibody, which determines its unique binding characteristics.
Antibody affinity refers to the strength of the binding interaction between a single antigen epitope and the paratope (binding site) of an antibody. This interaction is a fundamental measure of how well an antibody recognizes its specific antigen target.
Recombinant antibodies are produced using genetic engineering techniques, unlike traditional antibody production, where the immune system generates antibodies without direct control over their sequence. By introducing genes encoding antibody fragments into host cells, such as bacteria or mammalian cells, recombinant antibodies can be expressed, purified, and deployed for applications including research, diagnostics, and therapeutics.
Recombinant antibody expression is a biotechnological process that involves engineering and producing antibodies outside their natural context using recombinant DNA technology.
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