Immune Expression in Sentinel Lymph Node Biopsies Helps Predict Melanoma Outcomes

The expression of immune markers and T-cell subsets can help predict outcomes of sentinel lymph node (SLN)-positive melanoma patients, according to a new study presented at the Society for Melanoma Research 2015 International Congress, held November 18–21 in San Francisco.

SLN biopsy in melanoma patients is a highly accurate staging method and an important prognostic factor that requires a team approach, including nuclear medicine physicians, surgeons, and pathologists, said Hojabr Kakavand, a PhD candidate at the Melanoma Institute Australia, New South Wales, Australia. He noted that melanoma patients with SLN metastases have variable 5-year survival rates.

Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors have significantly improved clinical outcomes in unresectable metastatic melanoma, and are now being tested in the adjuvant setting in advanced-stage disease. However, the administration of adjuvant PD-1 or PD-L1 inhibitors in early-stage metastatic melanoma remains unclear, he said.

Tumor infiltrating lymphocytes (TILs) have been shown to have prognostic significance in primary melanoma and in melanoma metastases. The Cancer Genome Atlas Network recently found a large cohort demonstrating TIL grade is significantly associated with prognosis.

Kakavand and colleagues set out to characterize the infiltrate of immune cells into SLN melanoma metastases, determine tumor PD-L1 expression, and correlate melanoma features and immune cell subsets to outcome measures.

They analyzed SLNs containing metastatic melanoma from 60 treatment-naive patients, looking specifically for PD-1 (differentiation marker), PD-L1 (inhibitory ligand), CD3 (lymphocyte marker), CD4 (helper T cells), CD8 (cytotoxic T cells), and FOXP3 (regulatory T cells). These results were correlated with clinical and pathologic features and outcomes.

Tumoral PD-1 expression was present in 26 patients, but did not correlate with outcome. However, the researchers observed positive correlations between the number of CD3-positive, CD-4 positive, and CD8-positive TILs and recurrence-free and overall survival.

There was a negative correlation between the number of peritumoral PD-1–positive lymphocytes and recurrence-free and overall survival.

Based on these results, he said “expression of PD-L1 in SLN melanoma metastases provides a rationale for anti–PD-1 or anti–PD-L1 therapy in stage IIIA melanoma patients, particularly those with peritumoral PD-1–positive lymphocytes.”

In conclusion, Kakavand said: “This is the first study to demonstrate the prognostic significance of TILs in SLN metastases. High CD3-positive TILS, as well as CD4-positive and CD8-positive cells, are prognostic markers for longer recurrence-free and overall survival. High peritumoral PD-1–positive lymphocytes are a prognostic marker for shorter recurrence-free and overall survival. Tumor PD-L1 expression did not correlate with survival in this cohort.”

He believes these markers could provide information for the selection of patients to adjuvant checkpoint inhibitor clinical trials.

“We would like to combine as much information as possible about markers to provide useful tools for clinicians,” said Kakavand, in an interview. “These markers are available in routine pathological use. A pathologist looks at TILs and is able to provide important information on whether a patient will respond or not to CTLA and PD-L1 inhibitors. If the patient has no TILs, the patient will likely have no response to TIL therapy. The assessment of TILs is a useful tool in primary melanoma.”