(P 230) HIGHER BODY MASS INDEX IS ASSOCIATED WITH DECREASED CIRCULATING AND INTRATUMORAL NATURAL KILLER CELLS IN SOFT TISSUE SARCOMA

Objective: Natural killer (NK) cells are innate lymphocytes able to recognize and kill cancer cells as well as virally infected cells without prior antigen sensitization. We have previously observed improved survival in soft tissue sarcoma (STS) patients who harbor greater numbers of intratumoral NK cells. Obesity is an epidemic that has diverse effects on cancer progression and immune dysfunction. However, the impact of immune-modifying variables such as obesity on cancer outcomes and immune infiltrates in STS is not well-defined. Here, we sought to investigate the influence of obesity (using BMI) on NK cell populations in the blood and tumor of STS patients.

Methods: On an IRB-approved protocol, blood and tumor specimens were prospectively collected on 47 STS patients undergoing surgery from 2018 – 2023. Tumor tissue was harvested fresh, and mechanical digestion was performed to generate a single cell suspension. Blood and tumor specimens were processed for immune phenotyping by flow cytometry. Immune cells were identified by standard gating for singlets, live cells by nuclear viability stain, and CD45+ staining, followed by identification of the lymphocyte population by cell morphology using forward scatter/side scatter staining. CD3 versus CD56 bivariate plot was used to classify NK cells, T cells, and NKT populations. NK cells were further stratified into CD56bright vs CD56dim based on CD56 expression (“bright” being high positive expression, “dim” being low positive expression). Standard clinical and demographic data were extracted from the medical record. Standard statistical methods were used for analysis including parametric and nonparametric analyses for associations with outcomes (unpaired t test, correlations, PHREG survival analysis).

Results: Median age was 61 +/- 16 years. Sex was 40% female. Median tumor size was 13.2 +/- 9.5 cm in maximum dimension. 86% of patients were AJCC stage 3. The majority of tumors were located on the extremity (26, 55%), with 16 (34%) retroperitoneal and 5 (11%) located on the trunk. Histologic subtypes included (n, %): undifferentiated pleomorphic sarcoma (UPS) (9, 19.2%), leiomyosarcoma (6, 12.7%), liposarcoma (12, 25.5%), myxofibrosarcoma (MFS) (11, 23.4%), synovial sarcoma (5, 10.6%), desmoplastic small round cell tumor (1, 2.1%), epithelioid (1, 2.1%), malignant peripheral nerve sheath tumor (1, 2.1%), fibromyxoid (1, 2.1%), and rhabdomyosarcoma (1, 2.1%). The majority of tumors were high grade (43, 91.5%) followed by low grade (2, 4.3%) and intermediate grade (1, 2.1%). The majority of patients received neoadjuvant therapy with 29 (61.7%) receiving preoperative radiotherapy, 11 (23.4%) receiving pre-operative chemoradiation, and 1 (2.1%) receiving preoperative chemotherapy alone. 6 (12.8%) underwent upfront surgical resection. Median BMI was 26.9 with a total range of 18-39%.

Distant recurrence occurred in 17 (36%) patients. Death occurred in 7 (14.9%) of patients. Median follow up was 17.6 +/- 14.7 months. Distant recurrence free survival (DRFS) was 12.6 +/- 10.7 months. Overall survival was 25.5 +/- 15.2 months.

Cytotoxic CD56dim NK cells were more frequent in the blood (91.7% +/- 5.35) compared to tumor (82.4 +/- 12.5), unpaired t test, p=0.0001. CD56dim NK cells were more frequent in the peripheral blood of lean patients with BMI less than 25 (94.0%) compared to obese patients with BMI greater than 30 (89.4%), unpaired t test, p=0.014. Intratumoral NK cells were also more frequent in lean patients with BMI less than 25 compared to obese patients with BMI greater than 30, unpaired t test, p=0.03. Increasing BMI was associated with fewer NK cells in tumor (correlation, r=-0.46, p=0.048). Increasing BMI was also associated with fewer cytotoxic CD56dim NK cells in tumor (correlation, r=-0.51, p=0.03). Increasing BMI was associated with fewer months distant recurrence free survival (HR 1.140, p=0.037, 95% CI 1.008-1.290). There was no significant association between BMI and overall survival (HR 0.992, p=0.9266, 95% CI 0.838-1.175).

Conclusion: Obesity is associated with differences in numbers and phenotype of NK cell infiltrates in STS patients undergoing surgery. Obesity-associated NK dysfunction may be prognostically relevant in STS, and further studies should probe the effect of obesity on immune infiltrates and immune cell function.