Background: Aral lentiginous melanoma (ALM) constitutes the most common subtype of cutaneous melanoma (CM) among people with pigmented skin, accounting to up to 70% of cases. In a prior study of 44 patients with advanced, unresectable ALM treated with checkpoint inhibitors, we demonstrated differential response to checkpoint inhibitors by ethnicity with Hispanic patients having a higher response to therapy compared to non-Hispanic patients. Accumulating evidence suggests that tumor mutation burden (TMB) can predict the efficacy of immune checkpoint inhibitors (ICI) in solid malignancies, including cutaneous melanoma. ALM however has significantly lower TMB compared to cutaneous melanoma suggesting that there are other mechanisms outside of TMB driving this response. Here, expanding upon our prior work, we will examine outcomes in over 130 patients and report for the first time, the correlation between ethnicity and response to checkpoint inhibitors in the largest dataset to our knowledge of acral melanoma patients. Methods: This was a retrospective analysis of all advanced and metastatic ALM patients treated with anti-CTLA4 (ipilimumab) or anti-PD1 (pembrolizumab or nivolumab) ICI between March 2011 and January 2019 at the University of Texas MD Anderson Cancer Center, Texas. Clinical response, progression free and overall survival outcomes (PFS and OS) and their correlation to ethnicity and TMB will be evaluated. Objective response will be measured using RECIST 1.1. OS and PFS will be estimated using the Kaplan-Meier method, and differences between groups assessed using the log-rank test. Associations between OS and PFS and measures of interest will be determined using Cox proportional hazards regression models. Results: 132 patients with Stages III-IV ALM (III: 27% and IV: 73%) were included in the analysis. Median age was 66.6 years old (15.8-92.5) and 58% were men. 28 (21.2%) self-identified as Hispanic, 101 (76.5%) were non-Hispanic, and 3 (2.3%) did not provide their ethnicity. The best objective response rate (ORR) was 27 (20.4%), with 9 (6.8%) showing complete response (CR) and 18 (13.6%) showing partial response (PR). 48 (36.4%)patients received anti-PD1 based- therapy while 57 (43.2%) received anti-CTLA4 only. We will present immune phenotyping of both adaptive and innate immune arms to investigate further mechanisms of differential response. Conclusions: The data from our prior small retrospective study suggested that non-Hispanic patients with ALM had low response rates to CPI presumably due to low TMB while interestingly, Hispanic patients, despite relatively low TMB have high response rates paralleling those seen in the overall cutaneous melanoma population. This data will provide the rationale to design prospective studies to investigate further how tumor micro-environment varies with ethnicity.