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Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations.

Publication ,  Journal Article
Kugel, CH; Douglass, SM; Webster, MR; Kaur, A; Liu, Q; Yin, X; Weiss, SA; Darvishian, F; Al-Rohil, RN; Ndoye, A; Behera, R; Alicea, GM; Xu, W ...
Published in: Clin Cancer Res
November 1, 2018

Purpose: 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. Clin Cancer Res; 24(21); 5347-56. ©2018 AACR See related commentary by Pawelec, p. 5193.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 1, 2018

Volume

24

Issue

21

Start / End Page

5347 / 5356

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • T-Lymphocytes, Regulatory
  • Programmed Cell Death 1 Receptor
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice, Transgenic
  • Mice
  • Melanoma
  • Immunomodulation
 

Citation

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Chicago
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MLA
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Kugel, C. H., Douglass, S. M., Webster, M. R., Kaur, A., Liu, Q., Yin, X., … Weeraratna, A. T. (2018). Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations. Clin Cancer Res, 24(21), 5347–5356. https://doi.org/10.1158/1078-0432.CCR-18-1116
Kugel, Curtis H., Stephen M. Douglass, Marie R. Webster, Amanpreet Kaur, Qin Liu, Xiangfan Yin, Sarah A. Weiss, et al. “Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations.Clin Cancer Res 24, no. 21 (November 1, 2018): 5347–56. https://doi.org/10.1158/1078-0432.CCR-18-1116.
Kugel CH, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, et al. Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations. Clin Cancer Res. 2018 Nov 1;24(21):5347–56.
Kugel, Curtis H., et al. “Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations.Clin Cancer Res, vol. 24, no. 21, Nov. 2018, pp. 5347–56. Pubmed, doi:10.1158/1078-0432.CCR-18-1116.
Kugel CH, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, Weiss SA, Darvishian F, Al-Rohil RN, Ndoye A, Behera R, Alicea GM, Ecker BL, Fane M, Allegrezza MJ, Svoronos N, Kumar V, Wang DY, Somasundaram R, Hu-Lieskovan S, Ozgun A, Herlyn M, Conejo-Garcia JR, Gabrilovich D, Stone EL, Nowicki TS, Sosman J, Rai R, Carlino MS, Long GV, Marais R, Ribas A, Eroglu Z, Davies MA, Schilling B, Schadendorf D, Xu W, Amaravadi RK, Menzies AM, McQuade JL, Johnson DB, Osman I, Weeraratna AT. Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations. Clin Cancer Res. 2018 Nov 1;24(21):5347–5356.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 1, 2018

Volume

24

Issue

21

Start / End Page

5347 / 5356

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • T-Lymphocytes, Regulatory
  • Programmed Cell Death 1 Receptor
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice, Transgenic
  • Mice
  • Melanoma
  • Immunomodulation