Cancer Immunotherapy

Skin Cancer

Immunotherapy may be used to treat certain types of skin cancer under certain conditions, such as when cancer is advanced and/or surgery isn’t possible (see Anatomy of the Skin).

Skin cancer can develop anywhere on the body. Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States, with more than 20 subtypes and variants. Squamous cell carcinoma (SCC) is less common than BCC. It is sometimes called squamous cell carcinoma of the skin, cutaneous squamous cell carcinoma (cSCC) or squamous cell skin cancer to differentiate it from SCC that develops in other parts of the body. Sometimes skin cancer may have features of both basal cell and cSCC, and these are usually treated like a SCC.

There are several SCC subtypes and related forms. Actinic keratosis is a common skin condition also referred to as sun spots or age spots. These slow-growing lesions are most likely to appear on the face, balding scalp, forearms and backs of hands. Actinic keratosis is considered a pre-cancer because it sometimes progresses to become SCC. Immunomodulators are topical treatments approved to treat actinic keratosis.

Squamous cell skin cancer in situ (in SY-too), also called Bowen disease, is SCC in its very earliest form and involves only the superficial layer of skin. It grows very slowly, and without treatment, it may become SCC. Marjolin’s ulcer, which can be aggressive, is SCC that develops at the site of an old scar, burn or non-healing wound.

Merkel cell carcinoma (MCC) is among the many rare types, subtypes and variants of cancer that affect the skin. It forms in the top layer of skin near the nerve endings. Because MCC is highly aggressive, it grows rapidly and is likely to spread, first to nearby lymph nodes and then to distant areas. These may include skin and lymph nodes elsewhere in the body, the brain, lungs, bones and other organs. MCC may also be referred to as neuroendocrine carcinoma of the skin.

Four immune checkpoint inhibitors may be used in certain instances for people with non-melanoma skin cancer. Two treat Merkel cell carcinoma, and the other two are for cSCC. Treatment is currently approved for locally advanced or cSCC that has metastasized (spread to other parts of the body).

Although basal cell carcinomas have not responded well to immune checkpoint inhibitors, small BCCs have been treated with topical immunotherapy with good responses. This may be considered when surgery is not possible or may be difficult.

Understanding the Variety of Immunotherapy Options Available

Using immunotherapy to treat skin cancer is a significant leap forward. The introduction of this new class of drugs has changed how doctors treat these cancers, and it has improved the prognosis for many people with Stage III or IV disease.

Research has discovered multiple ways to harness the potential of the body’s own immune system and enable it to recognize and eliminate cancer cells. Today, several types of immunotherapy are approved to treat melanoma and other skin cancers, and all are a result of the research done in clinical trials.

Once considered a last resort for metastatic cancers, immunotherapy is often being used as a first-line therapy or second-line therapy. First-line therapy, also known as induction therapy, primary therapy and primary treatment, is the first treatment given and is usually part of the standard of care. Second-line therapy is treatment given after the primary treatment (first-line therapy) doesn’t work or stops working. Some may be used as systemic or local treatments. Systemic treatments travel throughout your body, and local treatments are injected into a lesion or applied topically to the skin.

For early stage skin cancer, treatment usually involves surgery only. For more advanced stages, additional treatment options may be necessary to prevent recurrence or to treat a metastasis. Immunotherapy strategies may be given after surgery (adjuvant treatment) with the goal of reducing the risk of disease recurrence. In more advanced cases or when the cancer is unresectable (unable to be removed with surgery), immunotherapy may be used as the first-line therapy. It may also be used in combination with other treatments such as chemotherapy, targeted therapy and radiation therapy.

Research in clinical trials is ongoing to determine if immunotherapy drugs approved for Stage III and IV cancers can be used in earlier stages and to discover new types of effective immunotherapy.

The following types of immunotherapy are approved to treat skin cancers.

Immune Checkpoint Inhibitors

This type of immunotherapy was first approved in 2011 for melanoma and in 2017 for other skin cancers. These drugs are given as an infusion intravenously (IV) and are systemic. Some immune checkpoint inhibitors are approved to be used alone or in combination.

To understand how immune checkpoint inhibitors work, it is helpful to know how the immune system works in general. Because one of the primary functions of the immune system is to determine which cells or substances are self (normal) or non-self (foreign), the immune system contains cells, called B-cells and T-cells, which can recognize the foreign cells. These cells are part of the white blood cells that fight infections and eliminate cancer cells in the body. To prevent attack on normal cells, the immune system has a complex process that regulates the activity of B-cells and T-cells. The immune cells are rapidly activated to clear an infection or kill a cancer cell. However, to prevent an attack on normal cells, the immune system must slow down. It does this through the use of checkpoints.

Checkpoints keep the immune system “in check” by turning off immune cells or killing the immune cells. This may be normal after an infection has been cleared, but, in cancer, this may occur prematurely, allowing the cancer to continue to grow. In addition to checkpoints found on immune cells, other cells called regulatory T-cells may also turn down activated immune cells. When the correct checkpoint proteins and cell receptors connect, a series of signals is sent to the immune system to slow down once an immune response is finished. So far, three checkpoint receptors that slow down the immune system have been identified for their roles in cancer treatment.

  1. CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a receptor that binds with certain molecules to tell the immune system to slow down.
  2. PD-1 (programmed cell death protein 1) is a receptor involved with telling T-cells to die and reducing the death of regulatory T-cells (suppressor T-cells). Both of these effects slow down an immune response. PD-1 can tell the immune system to slow down only if it connects with PD-L1.
  3. PD-L1 (programmed death-ligand 1) is a protein that, when combined with PD-1, sends a signal to reduce the production of T-cells and enable more T-cells to die.

When PD-1 (the receptor) and PD-L1 (the protein) combine, the reaction signals it’s time to slow down. CTLA-4, however, can connect with more than one protein, which is a more complex reaction than with PD-1 and PD-L1. When CTLA-4 combines with any of the various proteins, it also tells the immune system to slow down.

Checkpoint inhibiting drugs prevent connections between checkpoints. This prevents the immune response from slowing down, which allows the immune cells to continue fighting the cancer. When an immune checkpoint inhibitor is given, the immune system can better recognize cancer cells as foreign cells.

The following immune checkpoint inhibitors are currently approved as cancer treatments.

  • Anti-CTLA-4 antibodies allow T-cells to continue fighting cancer cells instead of shutting down.
  • Anti-PD-1 drugs allow for the continued or increased production of T-cells and enable them to continue fighting cancer.
  • Anti-PD-L1 molecules prevents the destruction of T cells allow the T-cells to recognize tumor cells as the enemy and then attack them.

The approved immune checkpoint inhibitors are monoclonal antibodies (mAbs). Antibodies (a type of protein) are the body’s way of tagging a specific antigen (foreign substance). They bind to the antigen, which allows the rest of the immune system to recognize the antigen as foreign and target it for destruction.

Laboratory-made antibodies that are designed to target specific tumor targets, such as antigens or other proteins found on the cancer cell, can work in different ways, including flagging targeted cancer cells for destruction, blocking growth signals and receptors, and delivering other therapeutic agents directly to targeted cancer cells. They can also be created to carry cancer drugs, radiation particles or laboratory-made cytokines (proteins that enable immune cells to send messages to each other) directly to cancer cells. Combining mAbs with radiation particles, a treatment known as radioimmunotherapy, allows for radiation to be delivered in lower doses over a longer period of time. This direct form of radiation delivery typically damages only the targeted cells.


Immunomodulatory drugs may stimulate or slow down the immune system in indirect ways. They may boost the immune system and the effects of other therapies on the tumor and the tumor microenvironment, slow or stop the growth of the tumor and its blood vessel formation, improve the bone marrow microenvironment and have an anti-inflammatory effect, slowing the growth of the cancer. They are generally considered systemic treatments, but some may be given directly into the cancer.


Two types of vaccines are used against cancer: preventive vaccines and treatment vaccines. A treatment vaccine that is injected into the body to create an immune response is currently being tested in patients with melanoma.


Identifying Biomarkers to Detect Response to Immunotherapy

Now that research has shown that most cancer is caused by genetic changes in DNA, detecting these changes at the microscopic level with biomarkers is becoming an increasingly valuable part of diagnosing and treating skin cancers. As a result, the use of biomarkers is expanding rapidly. Biomarkers are substances, such as genes, proteins or molecules, produced by cancer cells or other cells in the body. Biomarkers are also called tumor markers, molecular markers, biological markers or serum markers. Other biomarkers may be cells, especially immune cells. 

Biomarkers may be prognostic, predictive or diagnostic. A prognostic biomarker provides information about a person’s overall cancer outcome, regardless of therapy, while a predictive biomarker gives information about the effect of a specific treatment approach. Diagnostic biomarkers help determine the type of tumor.

The following biomarkers are currently being used by some doctors to make immunotherapy treatment decisions for melanoma and other skin cancers.

  • PD-L1 expression may be tested to determine if the tumor cells or immune cells in the tumor’s microenvironment contain a higher level, which may mean that a patient could be a good candidate for immune checkpoint inhibitors. However, testing this biomarker alone is not sufficient to determine a therapeutic response to immunotherapy in patients with skin cancers.
  • Tumor mutational burden (TMB) is an assessment of the number of genetic mutations in a tumor. It can help doctors determine if a patient will respond to immunotherapy. It is believed that the higher the TMB level is, the more likely the patient will respond to immunotherapy.

Not all patients who receive immunotherapy respond, and research is ongoing to find out why. Scientists are looking for more biomarkers that may indicate whether a patient is a good candidate for immunotherapy. Biomarkers are expected to be considered more commonly in the future so that immunotherapy is not given to someone who may not respond to it.