Pre-operative stereotactic radiosurgery and peri-operative dexamethasone for resectable brain metastases: a two-arm pilot study evaluating clinical outcomes and immunological correlates.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 Oct 2024
14 Oct 2024
Historique:
received:
01
07
2024
accepted:
29
09
2024
medline:
15
10
2024
pubmed:
15
10
2024
entrez:
14
10
2024
Statut:
epublish
Résumé
Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.
Identifiants
pubmed: 39402027
doi: 10.1038/s41467-024-53034-6
pii: 10.1038/s41467-024-53034-6
doi:
Substances chimiques
Dexamethasone
7S5I7G3JQL
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8854Informations de copyright
© 2024. The Author(s).
Références
Naito, Y. et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 58, 3491–3494 (1998).
pubmed: 9721846
Sharma, P. et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc. Natl Acad. Sci. USA 104, 3967–3972 (2007).
doi: 10.1073/pnas.0611618104
pubmed: 17360461
pmcid: 1820692
Hiraoka, K. et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br. J. Cancer 94, 275–280 (2006).
doi: 10.1038/sj.bjc.6602934
pubmed: 16421594
pmcid: 2361103
Dieci, M. V. et al. Immune characterization of breast cancer metastases: prognostic implications. Breast Cancer Res. 20, 62 (2018).
doi: 10.1186/s13058-018-1003-1
pubmed: 29929548
pmcid: 6013851
Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).
doi: 10.1038/nature19330
pubmed: 27501248
pmcid: 5297183
Luoma, A. M. et al. Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell 185, 2918–2935.e2929 (2022).
doi: 10.1016/j.cell.2022.06.018
pubmed: 35803260
pmcid: 9508682
Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).
doi: 10.1038/s41586-019-1836-5
pubmed: 31827286
pmcid: 7108171
Eberhardt, C. S. et al. Functional HPV-specific PD-1(+) stem-like CD8 T cells in head and neck cancer. Nature 597, 279–284 (2021).
doi: 10.1038/s41586-021-03862-z
pubmed: 34471285
pmcid: 10201342
Krishna, S. et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science 370, 1328–1334 (2020).
doi: 10.1126/science.abb9847
pubmed: 33303615
pmcid: 8883579
Sade-Feldman, M. et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 175, 998–1013.e1020 (2018).
doi: 10.1016/j.cell.2018.10.038
pubmed: 30388456
pmcid: 6641984
Brummelman, J. et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors. J. Exp. Med. 215, 2520–2535 (2018).
Prokhnevska, N. et al. CD8(+) T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor. Immunity 56, 107–124.e105 (2023).
doi: 10.1016/j.immuni.2022.12.002
pubmed: 36580918
Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).
Miller, B. C. et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).
doi: 10.1038/s41590-019-0312-6
pubmed: 30778252
pmcid: 6673650
Tabanelli, V. et al. The identification of TCF1+ progenitor exhausted T cells in THRLBCL may predict a better response to PD-1/PD-L1 blockade. Blood Adv. 6, 4634–4644 (2022).
doi: 10.1182/bloodadvances.2022007046
pubmed: 35767735
pmcid: 9636403
Alvarez, J. I. et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).
doi: 10.1126/science.1206936
pubmed: 22144466
Engelhardt, B. & Ransohoff, R. M. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579–589 (2012).
doi: 10.1016/j.it.2012.07.004
pubmed: 22926201
Shechter, R., London, A. & Schwartz, M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol. 13, 206–218 (2013).
doi: 10.1038/nri3391
pubmed: 23435332
Biermann, J. et al. Dissecting the treatment-naive ecosystem of human melanoma brain metastasis. Cell 185, 2591–2608.e2530 (2022).
doi: 10.1016/j.cell.2022.06.007
pubmed: 35803246
pmcid: 9677434
Karimi, E. et al. Single-cell spatial immune landscapes of primary and metastatic brain tumours. Nature 614, 555–563 (2023).
doi: 10.1038/s41586-022-05680-3
pubmed: 36725935
pmcid: 9931580
Brown, P. D. et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 18, 1049–1060 (2017).
doi: 10.1016/S1470-2045(17)30441-2
pubmed: 28687377
pmcid: 5568757
Mahajan, A. et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 18, 1040–1048 (2017).
doi: 10.1016/S1470-2045(17)30414-X
pubmed: 28687375
pmcid: 5560102
Prabhu, R. S. et al. Single-Fraction Versus Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM International Multicenter Cohort Study. Int. J. Radiat. Oncol. Biol. Phys. https://doi.org/10.1016/j.ijrobp.2023.09.012 (2023).
Tawbi, H. A. et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N. Engl. J. Med. 379, 722–730 (2018).
doi: 10.1056/NEJMoa1805453
pubmed: 30134131
pmcid: 8011001
Buchwald, Z. S. et al. Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy. J Immunother Cancer 8. https://doi.org/10.1136/jitc-2020-000867 (2020).
Sudmeier, L. J. et al. Distinct phenotypic states and spatial distribution of CD8(+) T cell clonotypes in human brain metastases. Cell Rep. Med. 3, 100620 (2022).
doi: 10.1016/j.xcrm.2022.100620
pubmed: 35584630
pmcid: 9133402
Acharya, N. et al. Endogenous glucocorticoid signaling regulates cd8(+) t cell differentiation and development of dysfunction in the tumor microenvironment. Immunity 53, 658–671.e656 (2020).
doi: 10.1016/j.immuni.2020.08.005
pubmed: 32937153
pmcid: 7682805
Giles, A. J. et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J. Immunother. Cancer 6, 51 (2018).
doi: 10.1186/s40425-018-0371-5
pubmed: 29891009
pmcid: 5996496
Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type i interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).
doi: 10.1016/j.immuni.2014.10.019
pubmed: 25517616
pmcid: 5155593
Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).
doi: 10.1038/nature14292
pubmed: 25754329
Chen, X. et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 615, 668–677 (2023).
doi: 10.1038/s41586-023-05788-0
pubmed: 36890231
pmcid: 10258627
Gonzalez, H. et al. Cellular architecture of human brain metastases. Cell 185, 729–745.e720 (2022).
doi: 10.1016/j.cell.2021.12.043
pubmed: 35063085
pmcid: 8857062
Klemm, F. et al. Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 181, 1643–1660.e1617 (2020).
doi: 10.1016/j.cell.2020.05.007
pubmed: 32470396
pmcid: 8558904
Friebel, E. et al. Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes. Cell 181, 1626–1642.e1620 (2020).
doi: 10.1016/j.cell.2020.04.055
pubmed: 32470397
Berghoff, A. S. et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 5, e1057388 (2016).
doi: 10.1080/2162402X.2015.1057388
pubmed: 26942067
Siddiqui, I. et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity 50, 195–211.e110 (2019).
doi: 10.1016/j.immuni.2018.12.021
pubmed: 30635237
Connolly, K. A. et al. A reservoir of stem-like CD8(+) T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci. Immunol. 6, eabg7836 (2021).
doi: 10.1126/sciimmunol.abg7836
pubmed: 34597124
pmcid: 8593910
Formenti, S. C. & Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl Cancer Inst. 105, 256–265 (2013).
doi: 10.1093/jnci/djs629
pubmed: 23291374
pmcid: 3576324
Golden, E. B., Demaria, S., Schiff, P. B., Chachoua, A. & Formenti, S. C. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol. Res. 1, 365–372 (2013).
doi: 10.1158/2326-6066.CIR-13-0115
pubmed: 24563870
pmcid: 3930458
Demaria, S. et al. Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose? J Immunother Cancer 9. https://doi.org/10.1136/jitc-2020-002038 (2021).
Berghoff, A. S. et al. Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology 66, 289–299 (2015).
doi: 10.1111/his.12537
pubmed: 25314639
Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355, 1423–1427 (2017).
doi: 10.1126/science.aaf0683
pubmed: 28280249
pmcid: 5595217
Minniti, G. et al. Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity. J. Immunother. Cancer 7, 102 (2019).
doi: 10.1186/s40425-019-0588-y
pubmed: 30975225
pmcid: 6458744
Lussier, D. M. et al. Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads. Proc Natl Acad Sci USA 118. https://doi.org/10.1073/pnas.2102611118 (2021).
Contal, C. & O’Quigley, J. An application of changepoint methods in studying the effect of age on survival in breast cancer. Comput. Stat. Data Anal. 30, 253–270 (1999).
doi: 10.1016/S0167-9473(98)00096-6