Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases

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Fife, C, Williams, J, James, F, Gregory, s ORCID: https://orcid.org/0000-0003-3484-2946, Andreou, T, Sunderland, A, McKimmie, C, Brownlie, RJ, Salmond, RJ, Heaton, S, Errington-Mais, F, Hadi, Z, Westhead, DR, Hall, M, Davie, A, Emmett, A and Lorger, M, 2024. Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases. Journal for ImmunoTherapy of Cancer, 12 (11): e009522. ISSN 2051-1426

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Official URL: https://doi.org/10.1136/jitc-2024-009522

Abstract

Background: Brain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) demonstrates intracranial efficacy in a proportion of patients with melanoma, the responses are rarely durable, particularly in patients with symptomatic BrM. The brain is an immune-specialized organ and immune responses are regulated differently to the periphery.

Methods: Using our previously established two-site model of melanoma BrM with concomitant intracranial and extracranial tumors, in which clinically observed efficacy of the combined PD-1/CTLA-4 (PC) blockade can be reproduced, we here explored the role of natural killer (NK) cells in BrM, using functional studies, immunophenotyping and molecular profiling.

Results: We demonstrate that NK cells are required for the intracranial efficacy of PC blockade. While both perforin and interferon gamma were necessary for the PC blockade-dependent control of intracranial tumor growth, NK cells isolated from intracranial tumors demonstrated only a limited cancer cell killing ability, and PC blockade did not alter the abundance of NK cells within tumors. However, the depletion of NK cells in PC blockade-treated mice led to tumor molecular profiles reminiscent of those observed in intracranial tumors that failed to respond to therapy. Furthermore, the depletion of NK cells resulted in a strikingly reduced abundance of CD8+ T cells within intracranial tumors, while the abundance of other immune cell populations including CD4+ T cells, macrophages and microglia remained unaltered. Adoptive T cell transfer experiments demonstrated that PC blockade-induced trafficking of CD8+ T cells to intracranial tumors was chemokine-dependent. In line with this, PC blockade enhanced intratumoral expression of several T cell-attracting chemokines and we observed high expression levels of cognate chemokine receptors on BrM-infiltrating CD8+ T cells in mice, as well as in human BrM. Importantly, the depletion of NK cells strikingly reduced the intratumoral expression levels of T cell attracting chemokines and vascular T cell entry receptors that were upregulated following PC blockade.

Conclusion: Our data demonstrate that NK cells underpin the efficacy of PC blockade in BrM by orchestrating the "responder" molecular profile in tumors, and by controlling the intratumoral abundance of CD8+ T cells through regulation of multiple key molecular mediators of T cell trafficking.

Item Type:	Journal article
Publication Title:	Journal for ImmunoTherapy of Cancer
Creators:	Fife, C., Williams, J., James, F., Gregory, S., Andreou, T., Sunderland, A., McKimmie, C., Brownlie, R.J., Salmond, R.J., Heaton, S., Errington-Mais, F., Hadi, Z., Westhead, D.R., Hall, M., Davie, A., Emmett, A. and Lorger, M.
Publisher:	BMJ
Date:	November 2024
Volume:	12
Number:	11
ISSN:	2051-1426
Identifiers:	Number Type N/A Patent 10.1136/jitc-2024-009522 DOI 2292380 Other
Rights:	© Author(s) (or their employer(s)) This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
Divisions:	Schools > School of Science and Technology
Record created by:	Jeremy Silvester
Date Added:	21 Nov 2024 09:17
Last Modified:	21 Nov 2024 09:17
URI:	https://irep.ntu.ac.uk/id/eprint/52629