PD-L1 and Tumour Mutational Burden (TMB) in Melanoma

Melanoma is a type of skin cancer that develops from melanocytes, the cells that give skin its color. When melanoma has spread beyond the skin, one of the most effective treatment approaches is immunotherapy, a group of drugs that help the body’s immune system find and attack cancer cells. Two biomarkers can indicate how likely a melanoma is to respond to immunotherapy: PD-L1 and tumor mutational burden (TMB). A “biomarker” is a measurable feature of cancer, such as a protein on the surface of cells or the number of genetic changes inside them, that provides doctors with information they cannot get from looking at the cells under the microscope alone.

This article will help you understand what PD-L1 and TMB results mean on a melanoma pathology report, why these tests are done, how they are performed, and how the results may guide treatment decisions. Neither result is an inherited change passed down in families. Both are features of melanoma itself, and their main purpose is to help the treatment team assess whether immunotherapy is likely to be effective. It is important to know from the start that in melanoma, these tests are used as supporting information rather than as a strict on-or-off switch for immunotherapy, because melanoma often responds to immunotherapy even when these markers are not strongly positive.

What PD-L1 testing looks for

PD-L1 (programmed death-ligand 1) is a protein that some cancer cells, including melanoma cells, display on their surface. PD-L1 acts like an “off switch” for the immune system. When PD-L1 on a cancer cell connects with a matching protein called PD-1 on an immune cell, it sends a signal that tells the immune cell to stand down. Cancers use this switch to hide from the immune system. PD-L1 testing measures how much of this off-switch protein the melanoma is producing.

A group of immunotherapy drugs called immune checkpoint inhibitors work by blocking this off switch, which frees the immune system to recognize and attack the cancer. In general, a melanoma that produces more PD-L1 is somewhat more likely to respond to these drugs. However, PD-L1 is only one piece of information. In melanoma specifically, the link between PD-L1 level and response is weaker than in some other cancers, and melanomas that produce little or no PD-L1 still frequently respond to immunotherapy. For this reason, a PD-L1 result is interpreted alongside other findings rather than on its own.

What tumor mutational burden (TMB) testing looks for

Tumor mutational burden, usually abbreviated as TMB, is a measurement of how many genetic changes (called mutations) are present in the DNA of a cancer. It is reported as the number of mutations per megabase, where a megabase is one million units of DNA. The more mutations a cancer carries, the more it tends to look abnormal and “foreign” to the immune system, because some of those mutations cause the cell to make unusual proteins that immune cells can recognize as targets.

This is why TMB matters for melanoma treatment. A melanoma with a high TMB presents the immune system with many targets, which makes it more likely to respond to immune checkpoint inhibitors. Melanoma is important in the history of this biomarker because skin melanomas consistently have among the highest TMB of any cancer. This is a direct result of damage from ultraviolet (UV) light in sunlight, which causes mutations to build up in skin cells over many years. The strong responses seen when melanoma was first treated with checkpoint inhibitors helped establish TMB as a useful concept across many cancer types.

Why PD-L1 and TMB testing are done in melanoma

PD-L1 and TMB are tested in melanoma because both provide information about how likely the cancer is to respond to immunotherapy, the group of drugs (immune checkpoint inhibitors) that help the immune system attack the cancer. PD-L1 is a protein on the surface of the melanoma cells, and TMB is a count of the genetic changes inside them; a higher level of either is associated with a greater chance of benefit from these drugs. Testing is most relevant when melanoma has spread to nearby lymph nodes or to distant organs (metastasis), because that is the setting in which immunotherapy is used.

It is worth understanding that in melanoma, immunotherapy is frequently considered regardless of the PD-L1 or TMB result, because melanoma responds to these drugs more often and across a wider range of marker levels than many other cancers. The treatment team uses PD-L1 and TMB as supporting information that adds to the overall picture rather than as a strict requirement. This is different from some cancers, where a specific PD-L1 threshold must be met before immunotherapy can be used. TMB also carries a special role: a drug called pembrolizumab is approved for any advanced solid tumor with a high TMB, defined as 10 or more mutations per megabase, regardless of where the cancer started. This is called a tumor-agnostic approval, meaning the drug is approved based on a molecular feature rather than the type of cancer.

How PD-L1 and TMB testing are performed in melanoma

PD-L1 and TMB are tested on a sample of the melanoma that has already been removed, so testing does not usually require an additional procedure. The same tissue taken at the time of biopsy or surgery, stored as a paraffin block, is used. The two markers are measured by different methods because one is a protein and the other is a count of genetic changes.

PD-L1 by immunohistochemistry (IHC) — PD-L1 is measured using immunohistochemistry, a method that uses an antibody to stain the PD-L1 protein on a thin slice of the tumor on a glass slide. A pathologist examines the slide and estimates how much of the protein is present. This is the same general method used to test PD-L1 in many other cancers.
TMB by next-generation sequencing (NGS) — TMB is measured using next-generation sequencing, a laboratory method that reads large portions of the tumor’s DNA and counts the number of mutations. Because counting mutations requires reading many genes at once, TMB cannot be measured by a simple single-gene test; it requires this broader sequencing approach.

How PD-L1 and TMB results are reported in melanoma

PD-L1 and TMB results describe how likely a melanoma is to respond to immunotherapy. PD-L1 is a surface protein measured by staining, and TMB is a count of genetic changes measured by sequencing, so they are reported differently in the pathology report.

PD-L1 positive or PD-L1 expression detected — The melanoma cells, the surrounding immune cells, or both show staining for the PD-L1 protein. The report usually gives a number, most often a percentage of cells that stain or a score. Different scoring systems and antibodies exist, so the report will state which one was used. A positive result indicates a somewhat higher chance of response to immunotherapy.
PD-L1 negative or low — Little or no PD-L1 protein was detected. In melanoma, this does not rule out a response to immunotherapy, because many PD-L1-negative melanomas still respond.
TMB-high — The melanoma carries a large number of mutations, defined as 10 or more mutations per megabase. This result indicates a greater likelihood of response to immune checkpoint inhibitors and, on its own, can qualify a patient for approval for tumor-agnostic pembrolizumab in the advanced setting.
TMB-low — The melanoma carries fewer mutations, below the 10-per-megabase threshold. Because most skin melanomas have a high TMB, a low result is less common and may prompt the team to consider whether the melanoma began elsewhere, such as on the palms, soles, under the nails, or on a mucous membrane, where TMB tends to be lower.

What PD-L1 and TMB results mean for melanoma treatment

The PD-L1 and TMB results in melanoma help the treatment team assess how likely the cancer is to respond to immunotherapy, a class of immune checkpoint inhibitor drugs that release the brakes on the immune system. PD-L1 reflects how much of an immune “off switch” protein the melanoma displays, and TMB reflects how many genetic changes it carries; higher levels of either point toward a greater chance of benefit. The pathology report does not prescribe treatment. Instead, these results are weighed alongside the stage of the cancer, the patient’s overall health, and other findings during the team’s discussion of options.

For melanoma that has spread, immune checkpoint inhibitors are a central treatment option. These include drugs that block PD-1 (pembrolizumab and nivolumab) and a drug that blocks a different immune off switch called CTLA-4 (ipilimumab). They may be used alone or in combination. Because melanoma responds to these drugs across a wide range of PD-L1 and TMB levels, immunotherapy is frequently considered even when these markers are low. A high TMB or a positive PD-L1 result adds confidence that immunotherapy is a reasonable choice, while a TMB-high result can also open the tumor-agnostic pembrolizumab pathway in the advanced setting.

These immunotherapy options are considered alongside other melanoma biomarkers. In particular, the melanoma’s BRAF mutation status determines whether a separate group of targeted drugs (BRAF and MEK inhibitors) is also an option; BRAF testing is described in a separate article. The medical oncology team decides, based on the full clinical picture, whether immunotherapy, targeted therapy, or a combination is the best fit and, if so, in what order.

Are PD-L1 and TMB results inherited?

Neither the PD-L1 result nor the TMB result in melanoma is inherited and is not passed down to children. PD-L1 expression reflects the behavior of melanoma cells and their interactions with the immune system; it is a feature of the tumor, not of the body’s other cells. TMB is a count of mutations that the melanoma acquired during a person’s lifetime, most often from years of UV light exposure, so these mutations are present only in the tumor and not in the rest of the body. Because both results describe the tumor rather than the genes a person is born with, they do not appear on a test for inherited cancer risk and have no implications for family members. This differs from other biomarkers, such as BRCA1 and BRCA2, which can be inherited.

What happens after PD-L1 and TMB testing

Once PD-L1 and TMB testing on the melanoma is complete, the results become part of the information the treatment team uses to plan care. PD-L1 is a surface protein, and TMB is a count of genetic changes; together, they help the team judge how likely the melanoma is to respond to immunotherapy. These results are considered alongside the stage of the cancer, whether it has spread to lymph nodes or distant organs, the BRAF mutation status, and the patient’s overall health.

Melanoma care usually involves a multidisciplinary team that may include a medical oncologist, a surgeon, a radiation oncologist, a dermatologist, and a pathologist. The medical oncologist typically leads decisions about systemic therapy, including whether immunotherapy is appropriate and whether it should be given alone or in combination. If immunotherapy is started, patients are monitored for response and immune-related side effects, which can occur because these drugs increase immune activity throughout the body. Regular imaging and follow-up visits are used to track how the melanoma is responding over time.

Questions to ask your doctor

Was my melanoma tested for PD-L1, tumor mutational burden, or both, and what were the results?
What scoring system and antibody were used for my PD-L1 test?
Was my TMB result high or low, and how many mutations per megabase were reported?
Do my PD-L1 and TMB results make immunotherapy a good option for me?
If my PD-L1 or TMB result is low, can I still benefit from immunotherapy?
How do my PD-L1 and TMB results fit together with my BRAF result and the stage of my melanoma?
Would you consider immunotherapy alone or a combination of immunotherapy drugs in my situation?
What immune-related side effects should I watch for, and how are they managed?
Does my TMB result qualify me for any treatment that is approved across cancer types?
Do my PD-L1 or TMB results have any meaning for my family members?