A Prime-Boost Vaccination Approach Induces Lung Resident Memory CD8+ T Cells Derived from Central Memory T Cells That Prevent Tumor Lung Metastasis

Our plain-English summary of A Prime-Boost Vaccination Approach Induces Lung Resident Memory CD8+ T Cells Derived from Central Memory T Cells That Prevent Tumor Lung Metastasis, by H. Xu, M. Yue, R. Zhou, et al (Cancer Research, 2024).

The study

• Authors: H. Xu, M. Yue, R. Zhou, P. Wang, M.Y. Wong, J. Wang, H. Huang, B. Chen, Y. Mo, R.C. Tam, B. Zhou, Z. Du, H. Huang, L. Liu, Z. Tan, K.Y. Yuen, Y. Song, H. Chen, Z. Chen
• Journal: Cancer Research
• Published: 2024;84(19):3173-3188
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (TRM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung TRM cells can help to improve strategies, preventing tumor metastasis. Here, we found that a prime-boost vaccination approach using intramuscular DNA vaccine priming, followed by intranasal live-attenuated influenza-vectored vaccine (LAIV) boosting induced higher frequencies of lung CD8+ TRM cells compared with other vaccination regimens. Vaccine-induced lung CD8+ TRM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (TCM) cells induced by the DNA vaccination were major precursors of lung TRM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of TCM cells for differentiation into TRM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit TCM cells via CXCR3-dependent chemotaxis and induced CD8+ TRM-associated transcriptional programs. These results identified TCM cells as the source of vaccine-induced CD8+ TRM cells that protect against lung metastasis. Significance: Prime-boost vaccination shapes the mucosal microenvironment and reprograms central memory T cells to generate lung resident memory T cells that protect against lung metastasis, providing insights for the optimization of vaccine strategies.

©2024 The Authors; Published by the American Association for Cancer Research.

In plain English

This was a laboratory experiment in mice. The authors compared six vaccination regimens using HIV-1 Gag as a model antigen; the main regimen (V1) was an intramuscular DNA-Gag prime followed by an intranasal live-attenuated influenza-vectored vaccine (LAIV-HK68-Gag) boost. Antigen-specific lung CD8+ tissue-resident memory (TRM) cells were detected only in intranasally boosted groups. After intravenous challenge with B16F10-Gag melanoma or AB1-Gag mesothelioma cells, only V1 significantly reduced melanoma lung metastasis and metastatic mesothelioma growth in the lungs. Depleting CD8+ T cells alone significantly impaired protection (P = 0.0352), whereas depleting CD4+ T cells alone did not (P = 0.4754). In parabiosis experiments sharing circulating memory T cells, vaccinated parabionts showed significantly less tumour growth than naive parabionts. Adoptively transferred central memory T (TCM) cells persisted and took on TRM features, while few transferred effector memory (TEM) cells were found; at day 2 after the boost, fewer CXCR3 knockout than wild-type TCM cells reached the lung, with no significant difference at day 14. Single-cell RNA sequencing showed residency gene signatures enriched in lung cytotoxic CD8+ T cells by day 2.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment in mice (vaccination regimens, tumour challenge, adoptive transfer, parabiosis, single-cell RNA sequencing)
• Who was studied: Six-to-ten week old male and female BALB/c, C57BL/6, OT-I, CD45.1 and CXCR3 knockout mice, housed at the University of Hong Kong; group sizes per experiment given in figure legends (e.g. n = 8 for V1, V2, V5; n = 6 for V6 in the melanoma challenge; n = 3 for sequencing)
• Exposure: Vaccination regimens: intramuscular electroporation DNA vaccine expressing HIV-1 Gag Mosaic (50 micrograms) priming, followed by intranasal or intramuscular live-attenuated influenza-vectored vaccine (LAIV-HK68-Gag or LAIV-CA04-Gag) boosting, compared with other prime-boost combinations (V1 to V6)
• Main results:
  • Antigen-specific lung CD8+ TRM cells were found only in groups boosted intranasally; intramuscular boosting elicited circulating memory (TEM and TCM) cells in lungs and mediastinal lymph node
  • Only the V1 regimen significantly inhibited melanoma lung metastasis, and in a separate experiment only V1 significantly inhibited metastatic mesothelioma growth in the lungs
  • In V1-vaccinated mice, depleting CD8+ T cells alone significantly impaired protection (P = 0.0352), while depleting CD4+ T cells alone did not (P = 0.4754)
  • In parabiosis, where circulating memory T cells were shared but only vaccinated animals retained TRM cells, vaccinated parabionts had significantly less tumour growth than naive parabionts, with tumour inhibition seen only in vaccinated parabionts at the earliest measurement (day 4)
  • Adoptively transferred CD8+ TCM cells persisted in lung, mediastinal lymph node and spleen after boosting and took on TEM and TRM phenotypes, whereas few transferred TEM cells were found in the tissues
  • At day 2 after intranasal vaccination, more wild-type than CXCR3 knockout OVA-specific CD8+ TCM cells were recruited to the lung, with no significant difference in the spleen; chemokines CXCL9, CXCL10 and CXCL11 messenger RNA and CXCL9/CXCL10 protein were increased in lungs of intranasally boosted mice
  • The CXCR3-dependent difference applied to early recruitment: the authors found no significant difference at day 14 after intranasal immunisation
  • Single-cell RNA sequencing showed core tissue-residency gene expression enriched in lung cytotoxic CD8+ T cells as early as day 2 after the intranasal boost
• The authors' conclusion: The authors concluded that their work showed a mechanism for lung CD8+ TRM-cell induction by systemic prime-mucosal boost immunisation, with TCM cells as the major precursors, and that this informs future vaccine optimisation
• Limitations the authors state:
  • The authors stated that their analysis described early transcriptional events in total TCM cells rather than only antigen-specific cells, and that future studies could use cell barcode techniques for higher resolution
  • The authors noted that, unlike flow cytometry, CD69 and ITGAE (CD103) in the sequencing data were insufficient to characterise lung CD8+ TRM cells, so signature gene sets had to be used
  • The authors acknowledged their finding that TCM cells are the main precursors appears discrepant with previous studies pointing to TEM cells, and allowed that vaccine-induced lung inflammation might later recruit TEM cells to replenish TRM cells

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Metastasis, Mesothelioma.

Related studies

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• Fowlpox-based survivin vaccination for malignant mesothelioma therapy — P. Bertino, M. Panigada, et al. (2013)
• Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells — Z. Yu, Z. Tan, et al. (2015)
• Neoadjuvant anti-tumor vaccination prior to surgery enhances survival — S.A. Fisher, A. Cleaver, et al. (2014)
• Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid — A. Scherpereel, B.D. Grigoriu, et al. (2013)

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