Age correlates with response to anti-pd1, reflecting age-related differences in intratumoral effector and regulatory t-cell populations.
AffiliationThe Wistar Institute, Philadelphia,
MetadataShow full item record
AbstractPurpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response.
CitationAge correlates with response to anti-pd1, reflecting age-related differences in intratumoral effector and regulatory t-cell populations. 2018, Clin Cancer Res
JournalClinical Cancer Research
- Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy.
- Authors: Chow MT, Ozga AJ, Servis RL, Frederick DT, Lo JA, Fisher DE, Freeman GJ, Boland GM, Luster AD
- Issue date: 2019 Jun 18
- Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells.
- Authors: Yoshida K, Okamoto M, Sasaki J, Kuroda C, Ishida H, Ueda K, Ideta H, Kamanaka T, Sobajima A, Takizawa T, Tanaka M, Aoki K, Uemura T, Kato H, Haniu H, Saito N
- Issue date: 2020 Jan 8
- PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8<sup>+</sup> T-Cell-Driven Antitumor Immunity.
- Authors: Buchan SL, Fallatah M, Thirdborough SM, Taraban VY, Rogel A, Thomas LJ, Penfold CA, He LZ, Curran MA, Keler T, Al-Shamkhani A
- Issue date: 2018 May 15
- Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration.
- Authors: Oweida A, Hararah MK, Phan A, Binder D, Bhatia S, Lennon S, Bukkapatnam S, Van Court B, Uyanga N, Darragh L, Kim HM, Raben D, Tan AC, Heasley L, Clambey E, Nemenoff R, Karam SD
- Issue date: 2018 Nov 1
- Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients.
- Authors: Kasanen H, Hernberg M, Mäkelä S, Brück O, Juteau S, Kohtamäki L, Ilander M, Mustjoki S, Kreutzman A
- Issue date: 2020 May