427 Cancer neutrophil encyclopedia: a deep dive into antigen-presenting warriors

Background

Neutrophils, the most efficient defenders against pathogens, are essential for tumor microenvironment balance and homeostasis.^1–3 However, given their plasticity and short half-life which made them too fragile to be profiled, it poses complex challenges regarding how neutrophils are imprinted and adapt specific fates across cancers.^4–7

Methods

Here we designed a one-two-punch sorting strategy, generated the neutrophil atlas from 225 samples of 144 patients from 17 cancer types, and further developed a computational pipeline to recover both shared and specific transcriptional programs^8–11 (figure 1).

Results

Unexpectedly, neutrophils harbored extraordinary complexity composed of 10 cell states and showed sharp tissue or phenotypic specialty. We observed and verified that cancer neutrophils are dramatically arranged along tumor-specific terminal differentiation paths such as inflammation, angiogenesis and antigen-presenting. In particular, the antigen-presenting program was associated with better patient outcomes in the majority of cancers. Such a program can be evoked by leucine metabolism and is dependent on mitochondrial remodeling, acetyl-CoA generation, and preferable epigenetic histone H3K27ac modification. Functionally, antigen-presenting neutrophils invoked expanded T cell response and neoantigen-specific reactiveness. We finally designed the antigen-presenting neutrophil immunotherapy (adoptive transferring and leucine diet) which fine-tunes the microenvironment balance and fuels anti-PD-1 immunotherapy.

Conclusions

In summary, these data not only lay the groundwork for future neutrophil research, and open the black box of neutrophil state divergence across cancers, but also unravel minimally invasive therapeutic opportunities including adoptive transferring antigen-presenting neutrophils.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (nos. 82130077, 81961128025, 82121002, and 82341008) to Q.G.; the National Natural Science Foundation of China (nos. 82394450, U23A6010) to J.F.; the National Natural Science Foundation of China (31925011) to L.Y.; The Research Projects from the Science and Technology Commission of Shanghai Municipality (nos. 21JC1410100, 21JC1401200, 20JC1418900, and 20YF1407400) to J.F., Q.G., and S.Z.; the Shanghai Municipal Science and Technology Major Project to Q.G.; the Strategic Priority Research Program (XDPB0303) of the Chinese Academy of Sciences, Program of Shanghai Academic Research Leader (23XD1404300), and the Shanghai Municipal Science and Technology Major Project (no. 2019SHZDZX02) to X.Z.; and the Science and Technology Commission of Shanghai Municipality (22ZR1479100) to S.J. We thank Claude Leclerc (Pasteur Institute), Andrew Zhu (Massachusetts General Hospital), Feng Wang, Jing Wang (Shanghai Institute of Immunology), Qunying Lei, Di Zhu, Liangqing Dong, Youpei Lin, Haichao Zhao, Xia Shen, Fanfan Fan, Shuaixi Yang, and Zijian Yang (Fudan University) for their support. We thank Shanghai Biochip Co., Ltd. for technical assistance. We thank the computing platform of the Medical Research Data Center of Shanghai Medical College Fudan University.

References

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Ethics Approval

We collected fresh samples from Zhongshan Hospital Fudan University with written consent and approval from the Institutional Review Board-approved protocols (B2021-381, B2021-084, B2020-348R, B2023-350).

Consent

Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.