γδ T cells impair airway macrophage differentiation in lung adenocarcinoma

Raffo-Iraolagoitia, X. L.; McFarlane, A. J.; Kruspig, B.; Fercoq, F.; Secklehner, J.; De Donatis, M.; Mackey, J. B. G.; Wiesheu, R.; Laing, S.; Hsieh, Y.-C.; Shaw, R.; Corbyn, R.; Nixon, C.; Miller, C.; Kirschner, K.; Bain, C. C.; Murphy, D. J.; Coffelt, S. B.; Carlin, L. M.

doi:10.1101/2023.09.14.557344

bioRxiv · 10.1101/2023.09.14.557344

γδ T cells impair airway macrophage differentiation in lung adenocarcinoma

Raffo-Iraolagoitia, X. L.·McFarlane, A. J.·Kruspig, B.·Fercoq, F.·Secklehner, J.·De Donatis, M.·Mackey, J. B. G.·Wiesheu, R.·Laing, S.·Hsieh, Y.-C.·Shaw, R.·Corbyn, R.·Nixon, C.·Miller, C.·Kirschner, K.·Bain, C. C.·Murphy, D. J.·Coffelt, S. B.·Carlin, L. M.

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Abstract

Protecting mucosal barriers, {gamma}{delta} T cells hold promise for the development of new cancer immunotherapies. In mice, {gamma}{delta} T cells can largely be segregated into CD27+ and CD27- cells, and their functions are modulated by interactions with surrounding cells. However, which cells communicate directly with {gamma}{delta} T cells in lung adenocarcinoma remains unknown. To address this, we combined flow cytometry, confocal microscopy, and scRNA-seq, using an autochthonous genetically engineered mouse model and different {gamma}{delta} T cell-deficient settings. We found that {gamma}{delta} T cells were increased in tumour-bearing lungs, with an altered phenotype. CD27- and CD27+ {gamma}{delta} T cells differed in their localisation and interactions including their tropism for macrophages. Overall, we propose a model where CD27+ {gamma}{delta} T cells undermine the differentiation of tumour-associated macrophages into airway macrophages, fostering a negative outcome in lung adenocarcinoma. Determining its translatability to human health may offer new avenues for immunotherapeutic strategies. SummaryGuardians of pulmonary homeostasis, {gamma}{delta} T cells remain enigmatic regarding their role in lung adenocarcinoma. Raffo-Iraolagoitia et al. report that a subset of {gamma}{delta} T cells impairs the differentiation of tumour-associated macrophages into airway macrophages, relevant for the outcome of lung adenocarcinoma. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/557344v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@e679f7org.highwire.dtl.DTLVardef@15152dforg.highwire.dtl.DTLVardef@17eaa5org.highwire.dtl.DTLVardef@2e0e47_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Raffo-Iraolagoitia, X. L., McFarlane, A. J., Kruspig, B., Fercoq, F., Secklehner, J., De Donatis, M., Mackey, J. B. G., Wiesheu, R., Laing, S., Hsieh, Y.-C., Shaw, R., Corbyn, R., Nixon, C., Miller, C., Kirschner, K., Bain, C. C., Murphy, D. J., Coffelt, S. B., Carlin, L. M.. 2023-09-16. γδ T cells impair airway macrophage differentiation in lung adenocarcinoma. https://doi.org/10.1101/2023.09.14.557344

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