Immunotherapy in surgical oncology

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The treatment of many cancers has changed significantly in recent decades, with improved long-term survival and quality of life for survivors. Although traditional treatment modalities such as cytotoxic chemotherapy, radiotherapy, and surgery retain a central role in treatment, there has been a gradual drift towards the use of treatments based on molecular targets as well as immunotherapy. Even though many of these novel therapies were traditionally reserved for patients with metastatic disease, there has been an increase in the use of upfront targeted therapy and immunotherapy for patients with localized and locoregional disease. In some very specific instances, such as in mismatch repair-deficient (dMMR) colorectal cancer, astounding results have been reported with the use of upfront immunotherapy1–3. With the changing landscape of cancer management, surgeons now more than ever need to understand the mechanisms of action and potential consequences of these new treatments. It is well established that the immune system has the ability to remove abnormal cells from the body, and thus prevent the development and progression of cancer4. This is reinforced by the fact that patients with impaired immune function and those on immunosuppressive medications are at increased risk of developing many malignancies5,6. In patients who develop cancer without a background of immune deficiency, the immune system is somehow being rendered ineffective, with the cancer cells evading detection by immune cells. Immunotherapy aims to reinstate the ability of the immune system to recognize and destroy cancer cells. Immunotherapy comes in many forms, including the use of cytokines, therapeutic cancer vaccines, and adoptive T cell therapy, but this article focuses on the more common types encountered in clinical practice, which tend to be immune checkpoint inhibitors. Immune checkpoints form part of the normal immune system and serve to protect normal cells from the inflammatory response. Once activated, the immune checkpoints downregulate T cell activation through complex intracellular signalling mechanisms, and hence dampen the immune response. It is believed that tumour cells interact with and engage immune checkpoints to switch off or reduce the immune response and thus evade detection by the immune system7. Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are key components of the immune checkpoint system. PD-1 is expressed on the surface of T cells and, once activated, downregulates the immune system. It is activated by its ligand, PD-L1, which is often overexpressed on the surface of malignant cells and hence helps these cells to evade the immune response (Fig. 1a). PD-1 inhibitors such as pembrolizumab and nivolumab, or PD-L1 inhibitors such as atezolizumab and durvalumab, prevent the interaction between PD-1 and PD-L1 by binding to their targeted receptor, and this in turn prevents the downstream intracellular signalling that normally inhibits the immune response (Fig. 1b). The result is an enhanced T cell response and increased antitumour activity8. PD-1 and PD-L1 inhibitors have been used with varying success in many cancers, such as those of the lung, breast, colon, rectum, oesophagus, bladder, prostate, and pancreas, and those arising from the biliary tract9–12. Not all patients respond well to PD-1 and PD-L1 inhibitors, however. Cancers with a high tumour mutational burden (TMB), those that are dMMR, the presence of tumour-infiltrating lymphocytes, and tumours that have high PD-L1 expression levels have been shown to be associated with a good response to treatment13,14. Mechanism of action of PD-1 and PD-L1 antibodies a Interaction between programmed death ligand 1 (PD-L1) on the tumour cell surface and programmed cell death protein 1 (PD-1) on the T cell surface results in inhibition of immune cell activation. b Antibodies to PD-L1 and PD-1 disrupt the interaction between the two cell surface proteins and this allows reactivation of T cells with an enhanced immune response against cancer cells. The mechanism of action of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors is slightly more complex. An antigen-presenting cell (APC) presents an antigen from a malignant cell in the form of a mutated self-protein to a T cell receptor on the surface of a T cell, initiating T cell activation. However, further co-stimulatory signals are required for appropriate signalling within the T cell to enable the full immune response and initiation of cancer cell destruction to occur. These co-stimulatory signals are typically stimulated by B7-1 and B7-2 proteins on the APC binding to CD28 molecules on the T cells. If there is enough CD28 binding to B7-1/B7-2, there will be T cell activation, T cell proliferation, increased T cell survival, and increased T cell differentiation, all of which contribute to an enhanced immune response against cancer cells. CTLA-4 is a protein that is similar in structure to CD28, but its affinity for binding to B7 is much greater than that of CD28. Unlike CD28, binding of CTLA-4 to B7 does not produce a stimulatory effect and in fact may even produce an inhibitory effect. This means that the ratio of CTLA-4–B7 binding to CD28–B7 binding determines the immune activity of T cells, and the greater the ratio of CTLA-4–B7 binding to CD28–B7 binding, the less active the immune cells are (Fig. 2a). CTLA-4 appears to be upregulated in some cancers thus providing cancer cells with a mechanism for immune evasion. The mechanism of action of anti-CTLA-4 antibodies is such that they disrupt CTLA-4–B7 binding and thus allow an increase in the ratio of CD28–B7 binding to CTLA-4–B7 binding (Fig. 2b). This in turn allows activation and proliferation of T cells and reduces regulatory T cell-mediated immunosuppression15. CTLA-4 inhibitors, such as ipilimumab, have become well known for their role in the treatment of malignant melanoma and, more recently, for the treatment of cancer of the lung, kidney, prostate, and head and neck16. Identifying biomarkers that predict response to CTLA-4 inhibitors has proven more difficult; however, some evidence suggests that those with a high TMB are more likely to get a good response, whereas significant or complete loss of major histocompatibility complex class 1 expression on cancer cell membranes may predict resistance to treatment17,18. Mechanism of action of CTLA-4 antibodies a After the cancer antigen has been presented to the T cell receptor, further co-stimulatory signals in the form of CD28 binding to B7 are required to activate the immune system to mount a response toward the cancer cells. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) binding to B7 inhibits activation of the immune system by sending competing intracellular signals to decrease immune cell activation. b Antibodies to CTLA-4 block CTLA-4 and B7 binding. This allows the intracellular signalling from CD28 and B7 binding to become dominant, with the result of T cell activation, proliferation, and survival. This in turn allows T cells to attack cancer cells. TCR, T cell receptor; MHC, major histocompatibility complex. Although the role of immunotherapy in metastatic disease is becoming clearer, the precise role of immunotherapy in early cancers is controversial. Regardless of where and when it is used, surgeons need to be aware of the mechanisms of action, likely therapeutic effect, potential side-effects, and the significance of these drugs when used in close proximity to surgery. Despite early reports of excellent responses to immunotherapy and growing support of watch-and-wait approaches after a cCR, it should be remembered that these medications are suitable only for subsets of patients, and the long-term risk of local and distant recurrence is yet to be determined. For now, surgery will continue to play a core role in the management of many malignancies, but surgeons need to have a clear understanding of th

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