Background: Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with melanoma. There are still lots of patients could not reach the clinical benefit, even though with the positive expression of the programmed cell death 1 ligand 1 (PD-L1). Here, we aimed to research the immune resistance mechanism in melanoma.

Methods: The genomic data and clinical data of the discovery cohort was obtained from The Cancer Genome Atlas (TCGA). The clinical data of validation cohort in melanoma treated by immunotherapy was retrospective collected. And tissue from patients with melanoma were performed to whole exome sequencing in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab.

Results: Activation of WNT signaling was inferred that somatic mutations or somatic copy number alterations in WNT signaling elements including APC, WNT1, WNT4, WNT6, WNT16, CTNNB1, BCL9L, SMAD3 and SMAD4. Two cohort have been enrolled in this study, the discovery cohort from TCGA, and the validation cohort from the Chinese patients with melanoma. The frequency of WNT pathway alterations from the TCGA cohort was 28.4%, and which was represented mutually exclusive molecular subsets. In TCGA cohort, activating alteration WNT signaling were associated with shorter median OS (22.5 vs 13.6 months, p=0.047, HR=0.61 (0.37-0.89)).

Conclusions: Mutations predicted to activate the WNT pathway were associated with innate resistance to immune checkpoint blockade in melanoma.

Citation Format: Fuyu Gong, Yuezong Bai, wenzhuan Xie, Chuanliang Cui. WNT signal pathway activation correlates with innate resistant to immune checkpoint therapies in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1674.