Revealing the evolution of the tumor immune microenvironment in follicular lymphoma patients progressing within 24 months using single-cell imaging mass cytometry

Long Liu; Xingxing Yu; Zhifeng Li; Xiaohua He; Jie Zha; Zhijuan Lin; Yan Hong; Huijian Zheng; Qian Lai; Kaiyang Ding; Xian Jia; Guo Fu; Haifeng Yu; Haiyan Yang; Zhiming Li; Ken H Young; Bing Xu

doi:10.1186/s13045-022-01326-z

Revealing the evolution of the tumor immune microenvironment in follicular lymphoma patients progressing within 24 months using single-cell imaging mass cytometry

J Hematol Oncol. 2022 Aug 22;15(1):115. doi: 10.1186/s13045-022-01326-z.

Authors

Long Liu^#^{1

2}, Xingxing Yu^#^{1

2}, Zhifeng Li^#^{1

2}, Xiaohua He^#³, Jie Zha^#^{1

2}, Zhijuan Lin^#^{1

2}, Yan Hong^#^{1

2}, Huijian Zheng^{1

2}, Qian Lai^{1

2}, Kaiyang Ding⁴, Xian Jia⁵, Guo Fu⁵, Haifeng Yu^{6

7}, Haiyan Yang^{6

7}, Zhiming Li⁸, Ken H Young^{9

10}, Bing Xu^{11

12}

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, People's Republic of China.
² Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, People's Republic of China.
³ Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, People's Republic of China.
⁴ Department of Hematology, The First Affiliated Hospital of USTC Anhui Provincial Hospital, Hefei, 230001, People's Republic of China.
⁵ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005, People's Republic of China.
⁶ Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, 310012, People's Republic of China.
⁷ Department of Lymphoma, Institute of Cancer, and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, 310012, People's Republic of China.
⁸ Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, People's Republic of China. lizhm@sysucc.org.cn.
⁹ Hematopathology Division, Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA. ken.young@duke.edu.
¹⁰ Duke University Cancer Institute, Durham, NC, USA. ken.young@duke.edu.
¹¹ Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, People's Republic of China. xubing@xmu.edu.cn.
¹² Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, People's Republic of China. xubing@xmu.edu.cn.

^# Contributed equally.

Abstract

Background: Patients with follicular lymphoma (FL) who experience disease progression within 24 months (POD24) have inferior outcomes. The tumor immune microenvironment (TIME) plays a crucial role in pathogenesis and progression of follicular lymphoma (FL). However, TIME evolution during progression of disease within 24 months (POD24) is elusive.

Methods: Spatially resolved and single-cell image mass cytometry with a panel of 36 metal-tagged antibodies was used to quantitatively analyze the TIME structure in 13 paired FLs at diagnosis and POD24.

Results: Follicles and peri-follicular regions were well dissected in structure. Peri-follicular regions represented a barrier for immune infiltration into the follicles. More FL-cells in the peri-follicular regions suffered CD8⁺T cells attacks under simultaneous protection of regulatory T cells (Tregs) and/or macrophages compared with that in the follicles irrespective of POD24. During POD24, increased CD163^- macrophages with PD-1 ligand upregulation and decreased CD8⁺T cells with upregulated LAG-3 expression around FL-cells were observed in the follicles. Spatial analyses demonstrated that FL-cells interacted more intimately with macrophages than with Tregs and less with cytotoxic T cells in both peri-follicular regions and follicles during POD24. In comparison, macrophages also cooperated more frequently with Tregs to simultaneously hijack FL-cells, creating an enhanced immunosuppressive environment in both peri-follicular and follicular regions during POD24.

Conclusions: Peri-follicular regions function as a barrier by recruiting both CD8⁺T cells and immunosuppressive cells, protecting follicular FL-cells from immune attack at diagnosis or POD24. FL-cells reside in a more immune-compromised microenvironment and evade immune cell attacks during POD24. Novel immunotherapeutic approaches harnessing LAG-3, macrophages, and Tregs will be empowered to overcome poor outcomes in patients with FL POD24.

Keywords: FL; Immune signature; POD; T cells; TIME.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Disease Progression
Humans
Image Cytometry
Immunosuppressive Agents / therapeutic use
Lymphoma, Follicular* / drug therapy
Tumor Microenvironment

Substances

Immunosuppressive Agents