Lipid Droplet-Related PLIN2 in CD68+ Tumor-Associated Macrophage of Oral Squamous Cell Carcinoma: Implications for Cancer Prognosis and Immunotherapy

Abstract

BackgroundPLIN2 (adipose differentiation-related protein) belongs to the perilipin family and is a marker of lipid droplets (LDs). Numerous types of tumor exhibit a high PLIN2 level, but its tumorigenic or tumor-suppressive role has been in debate. Recently, LDs serve as innate immune hubs and show antimicrobial capacity. We here aimed to investigate the heterogeneous functions of PLIN2 in the tumor microenvironment and immune regulation.MethodsThis retrospective study included 96 oral squamous cell carcinoma (OSCC) samples and analyzed the spatial distribution of PLIN2 by immunohistochemistry (IHC) and LD level by oil red O staining. A total of 21 serial sections were obtained to analyze the relationship between PLIN2 and immune cells by IHC and immunofluorescence (IF). Single-cell sequencing was used to analyze the cell locations of PLIN2. The values of diagnosis and prognosis of PLIN2 were also evaluated. Tumor Immune Estimation Resource (TIMER), cBioPortal databases, and IHC analysis were used to investigate the relationship between PLIN2 and OSCC immune microenvironment.ResultsPLIN2 was mainly expressed in tumor-infiltrating immunocytes (TIIs) of OSCC. Patients with high PLIN2 harbored more cytoplastic LDs. CD68+ tumor-associated macrophages (TAMs), instead of T cells and B cells, were found to be the main resource of PLIN2 in OSCC stroma and lung, pancreas, prostate, and testis. However, CD56+ NK cells also showed less extent of PLIN2 staining in OSCC. Moreover, patients with a high PLIN2 level in immune cells had a higher TNM stage and were susceptible to postoperative metastasis, but the escalated PLIN2 level in invasive tumor front independently predicted shorter metastasis-free survival. Furthermore, a high PLIN2 presentation in the microenvironment induced immune suppression which was featured as less infiltration of CD8+ T cells and more CD68+ TAMs and Foxp3+ Tregs, accompanied by more immune checkpoint molecules such as CSF1R, LGALS9, IL-10, CTLA-4, and TIGIT.ConclusionCD68+ TAM-derived PLIN2 might participate in regulating immune balance of OSCC patients, which provides new insight into immune checkpoint therapy.

Prognostic and clinicopathologic significance of PLIN2 in cancers: A systematic review with meta-analysis

“…49 It exerts tumorigenic or tumor suppressive effects in a tumor-dependent manner. 46 As mentioned above, PLIN2 is associated with a poor prognosis in most cancers. However, other studies, as well as our systematic review and meta-analysis, suggest that inhibition of PLIN2 promotes tumor cell proliferation, tissue entry, and distant metastasis in ccRCC, uterine leiomyoma, 29 and HB.…”

“…The included studies used quantitative real-time-polymerase chain reaction or immunohistochemistry to detect the expression level of PLIN2, and all patients were divided into high or low PLIN2 expression groups by cutoff value. In the included studies, there were 10 different malignancies: breast cancer, [34][35][36][37][38] ccRCC, 18,39,40 cutaneous malignant melanoma, 41 HB, 19 hepatocellular carcinoma, 42 highgrade serous ovarian carcinoma, 43 lung adenocarcinomas, 44,45 oral squamous cell carcinoma, 46 pancreatic ductal adenocarcinoma, 47 and salivary duct carcinoma. 48 The result of analysis of survival data from the included studies were obtained following patients for 40-300 months.…”

Supervised discovery of interpretable gene programs from single-cell data

“…8e ). Individual invasion program genes are coherently expressed in macrophages, only increase in non-responders, and include known invasion and metastasis mediators ( CTSL 5 9 , CTSD 60 , CTSB 61 , CHI3L1 62 , SPP1 63 , PLIN2 64 ). Moreover, the invasion program includes cholesterol metabolism genes ( APOE 65,66 , APOC1 67 , CYP27A1 68 , GPNMB 69 ), some which have been linked to the suppression of inflammatory cytokine release (IL-6, TNF-alpha).…”

Metabolic Pathways as a Novel Landscape in Pancreatic Ductal Adenocarcinoma

“…Notably, PLIN2 is expressed in other cell types, such as monocytes and macrophages [ 118 ], where its expression was positively correlated with LGALS9 in PDAC; this protein converts polarized macrophages into an M2 phenotype, leading to the inhibited secretion of T-cell cytokines [ 119 ]. These findings suggest that PLIN2 might participate in immunomodulatory effects by regulating tumor-associated macrophages in the tumor microenvironment [ 120 ]. A high-fat diet was able to ameliorate mutated KRAS activity, increasing fibrosis and enhancing PDAC progression in a mouse model [ 121 ], and a recent study with an in vivo mouse model showed a causal and positive correlation between obesity and early PDAC progression, identifying altered beta cell expression of cholecystokinin (Cck) in response to obesity and defining islet Cck as a promoter in oncogenic KRAS-driven PDAC [ 122 ].…”