Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: A pilot study

Yong Qin, Mariana Petaccia de Macedo, Alexandre Reuben, Marie-Andrée Forget, Cara Haymaker, Chantale Bernatchez, Christine N Spencer, Vancheswaran Gopalakrishnan, Sujan Reddy, Zachary A Cooper, Orenthial J Fulbright, Renjith Ramachandran, Arely Wahl, Esteban Flores, Shawne T Thorsen, Rene J Tavera, Claudius Conrad, Michelle D Williams, Michael T Tetzlaff, Wei-Lien Wang, Dan S Gombos, Bita Esmaeli, Rodabe N Amaria, Patrick Hwu, Jennifer A Wargo, Alexander J Lazar, Sapna P Patel, Yong Qin, Mariana Petaccia de Macedo, Alexandre Reuben, Marie-Andrée Forget, Cara Haymaker, Chantale Bernatchez, Christine N Spencer, Vancheswaran Gopalakrishnan, Sujan Reddy, Zachary A Cooper, Orenthial J Fulbright, Renjith Ramachandran, Arely Wahl, Esteban Flores, Shawne T Thorsen, Rene J Tavera, Claudius Conrad, Michelle D Williams, Michael T Tetzlaff, Wei-Lien Wang, Dan S Gombos, Bita Esmaeli, Rodabe N Amaria, Patrick Hwu, Jennifer A Wargo, Alexander J Lazar, Sapna P Patel

Abstract

The low response rates to immunotherapy in uveal melanoma (UM) sharply contrast with reputable response rates in cutaneous melanoma (CM) patients. To characterize the mechanisms responsible for resistance to immunotherapy in UM, we performed immune profiling in tumors from 10 metastatic UM patients and 10 metastatic CM patients by immunohistochemistry (IHC). Although there is no difference in infiltrating CD8+ T cells between UM and CM, a significant decrease in programmed death-1 (PD-1)-positive lymphocytes was observed and lower levels of programmed death ligand-1 (PD-L1) in UM metastases compared with CM metastases. Tumors from metastatic UM patients showed a lower success rate of tumor-infiltrating lymphocyte (TIL) growth compared with metastatic CM (45% vs. 64% success), with a significantly lower quantity of UM TIL expanded overall. These studies suggest that UM and CM are immunologically distinct, and provide potential explanation for the impaired success of immunotherapy in UM.

Keywords: Cutaneous melanoma; immune profile; tumor infiltrating lymphocytes; uveal melanoma.

Figures

Figure 1.
Figure 1.
Decreased PD-1 and PD-L1 expression in UM metastases. (A) Representative IHC for CD8, PD-1, and PD-L1 in UM and CM metastatic tissues. Quantification of CD8 (B), PD-1 (C), and PD-L1 (D) in UM and CM metastases as counts/mm2 (B-C) and % positivity (D). Each dot represents a sample. Green, PD-L1-positive; Purple, PD-L1-negative. Statistical comparison between UM and CM cohorts was performed using non-parametric Mann-Whitney test (B-C) and Chi-square test (D).
Figure 2.
Figure 2.
Impaired TIL expansion for UM metastases. TIL culture was attempted from 655 CM and 33 UM Stage IIIC or Stage IV tumors. (A) Shown is success rate of deriving at least 40 million TIL from these cultures in UM (left) and CM (right) metastases. (B) Total number of TIL expanded in UM and CM metastases. TIL were cultured from tumor explants for 3–5 weeks and cells were counted at the end of the culture. Statistical comparison between UM and CM cohorts was performed using (A) Chi-square test and (B) non-parametric Mann–Whitney test; *p = 0.05; ****p < 0.0001.

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