Tumor-Infiltrating Lymphocytes in Necrotic Tumors after Melanoma Neoadjuvant Anti–PD-1 Therapy Correlate with Pathologic Response and Recurrence-Free Survival

Neoadjuvant anti–PD-1 therapy in melanoma may increase tumor-infiltrating lymphocytes (TIL), and more TIL are associated with better treatment response. A major pathologic response (MPR) in melanoma after neoadjuvant anti–PD-1 therapy usually comprises tumor necrosis and fibrosis. The role of TIL in necrotic tumor necrosis (nTIL) has not been explored.

We performed CD3 and CD8 IHC stains on 41 melanomas with geographic necrosis. Of the 41, 14 were immunotherapy-naïve, and 27 had been treated with one dose of neoadjuvant anti–PD-1 in two clinical trials. CD3⁺ and CD8⁺ nTIL were graded as absent/minimal or moderate/brisk. The percentage of necrotic areas in the tumor bed before and after treatment was quantified. The endpoints were MPR and 5-year recurrence-free survival (RFS).

In the immunotherapy-naïve cohort, 3/14 (21%) specimens had moderate/brisk CD3⁺, and 2/14 (14%) had moderate/brisk CD8⁺ nTIL. In the treated cohort, 16/27 (59%) specimens had moderate/brisk CD3⁺, and 15/27 (56%) had moderate/brisk CD8⁺ nTIL, higher than those of the naïve cohort (CD3, P = 0.046; CD8, P = 0.018). Tumor necrosis was significantly increased after anti–PD-1 therapy (P = 0.007). In the treated cohort, moderate/brisk CD3⁺ and CD8⁺ nTIL correlated with MPR (P = 0.042; P = 0.019, respectively). Treated patients with moderate/brisk CD3⁺ nTIL had higher 5-year RFS than those with absent/minimal nTIL (69% vs. 0%; P = 0.006). This persisted on multivariate analysis (HR, 0.16; 95% confidence interval, 0.03–0.84; P = 0.03), adjusted for pathologic response, which was borderline significant (HR, 0.26; 95% confidence interval, 0.07–1.01; P = 0.051).

CD3⁺ and CD8⁺ nTIL are associated with pathologic response and 5-year RFS in patients with melanoma after neoadjuvant anti–PD-1 therapy.