Low-dose radiotherapy promotes the formation of tertiary lymphoid structures in lung adenocarcinoma

Duo Wang; Liuying Huang; Danqi Qian; Yulin Cao; Xiaohan Wu; Peiwen Xu; Liang Ming; Junhui Tang; Zhaohui Huang; Yuan Yin; Leyuan Zhou

doi:10.3389/fimmu.2023.1334408

Low-dose radiotherapy promotes the formation of tertiary lymphoid structures in lung adenocarcinoma

Front Immunol. 2024 Jan 8:14:1334408. doi: 10.3389/fimmu.2023.1334408. eCollection 2023.

Authors

Duo Wang^{1

2}, Liuying Huang^{1

2}, Danqi Qian², Yulin Cao¹, Xiaohan Wu¹, Peiwen Xu¹, Liang Ming¹, Junhui Tang¹, Zhaohui Huang¹, Yuan Yin¹, Leyuan Zhou^{2

3

4}

Affiliations

¹ Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China.
² Department of Radiation Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China.
³ Department of Radiation Oncology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, China.
⁴ State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China.

Abstract

Purpose: A tertiary lymphoid structure (TLS) refers to an organized infiltration of immune cells that is linked to a positive prognosis and improved response to immunotherapy. However, methods that promote TLS formation are limited and challenging to implement in clinical settings. In this study, we aimed to promote the formation and maturation of TLSs in lung adenocarcinoma (LUAD) by combining low-dose radiotherapy (LDRT) with immunotherapy.

Methods: Tissue sections from 198 patients who had undergone surgery were examined. Risk factors for patient survival were assessed, and the relationship between TLSs and five-year survival was analyzed. The Kras-LSL-G12D spontaneous lung cancer mouse model was used to screen the optimal irradiation dose (0/1/2 Gy whole lung irradiation) for promoting TLS formation. LDRT combined with anti-PD-1 was used to promote the formation and maturation of TLSs.

Results: TLS+, TLS^High, TLS+GC+ and CD8^High within TLS+ were associated with a favorable prognosis. LDRT increased the formation of early TLSs in the Kras-LSL-G12D lung cancer mouse model. In addition, LDRT combined with anti-PD-1 treatment can significantly improve the maturity of TLSs in mouse LUAD, resulting in greater antitumor effects. This antitumor effect was strongly associated with the number of CD8+ T cells within the TLSs.

Conclusion: We successfully applied LDRT combined with PD-1 inhibitor therapy for the first time, which increased both the quantity and maturity of TLSs in lung cancer. This approach achieved a promising antitumor effect.

Keywords: immunotherapy; low dose radiotherapy; lung cancer; tertiary lymphoid structures; tumor microenvironment.

Publication types

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

MeSH terms

Adenocarcinoma of Lung* / radiotherapy
Adenocarcinoma* / radiotherapy
Animals
Disease Models, Animal
Humans
Lung Neoplasms* / radiotherapy
Mice
Proto-Oncogene Proteins p21(ras) / genetics
Tertiary Lymphoid Structures*

Substances

Proto-Oncogene Proteins p21(ras)

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by National Natural Science Foundation of China (No. 82173193); Science and Technology Demonstration Project of Social Development of Jiangsu Province (No. BE2019631); the Natural Science Foundation of Jiangsu Province (No. BK20211033); the Project of State Key Laboratory of Radiation Medicine and Protection, Soochow University (No. GZK1202202); the Gusu Talent Program(2023)007; the Double Hundred Medical Professionals Program of Wuxi (Nos. BJ2020053 and BJ2020058); and the Wuxi Taihu Lake Talent Plan, Wuxi Medical Key Discipline (No. ZDXK2021002).