Induced Tumor Heterogeneity Reveals Factors Informing Radiation and Immunotherapy Combinations.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 06 2020
15 06 2020
Historique:
received:
26
12
2019
revised:
17
02
2020
accepted:
20
02
2020
pubmed:
27
2
2020
medline:
14
9
2021
entrez:
27
2
2020
Statut:
ppublish
Résumé
To investigate how induced tumor heterogeneity influences immune responses to radiotherapy with different proportions of mixed immune-responsive and unresponsive tumor cells in a triple-negative breast cancer model. It is hypothesized that studying the immune environment of mixed tumors and responses to radiotherapy could nominate immune active therapies to enhance immune responses after radiotherapy. Evaluate efficacy and immune responses generated by radiotherapy in tumors with different proportions of immunologically responsive and unresponsive tumor cells. Then study the cellular responses and transcriptomic differences between the tumors to nominate immunotherapy combinations with radiotherapy and evaluate the combination. The addition of the responsive cells to unresponsive tumors led to a greater than expected therapeutic response to radiotherapy with both innate and adaptive immune components. There was a distinct change in myeloid cells, greater inflammatory macrophage activity, and enhanced antigen presentation with responsive cells after radiotherapy. Because differences in matrix components, cell adhesion biology, and innate immune signaling correlated with myeloid cell response and phenotype, we hypothesized that radiotherapy combined with CD40 agonist antibody would sensitize unresponsive tumors. The combination therapy resulted in improved innate and adaptive immune response. Importantly, CD40 treatment increased tumor response to radiotherapy and protected against metastatic spread in a metastatic model. These data combined with transcriptomics from human patients support radiotherapy and myeloid cell targeting for immunologically cold tumors. The established study model presents opportunities to investigate the complex overlapping biologic mechanisms that limit immunotherapy and to implement radiotherapy with different immunotherapy combinations.
Identifiants
pubmed: 32098769
pii: 1078-0432.CCR-19-4220
doi: 10.1158/1078-0432.CCR-19-4220
pmc: PMC7311370
mid: NIHMS1567435
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2972-2985Subventions
Organisme : Medical Research Council
ID : MC_UU_00001/8
Pays : United Kingdom
Organisme : NIDCR NIH HHS
ID : R03 DE014638
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA121940
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197713
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA118182
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA088035
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA079130
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA201304
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA067166
Pays : United States
Organisme : Cancer Research UK
ID : 28736
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R00 CA201304
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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