Microenvironment-Dependent Gradient of CTL Exhaustion in the AE17sOVA Murine Mesothelioma Tumor Model

Our plain-English summary of Microenvironment-Dependent Gradient of CTL Exhaustion in the AE17sOVA Murine Mesothelioma Tumor Model, by J.L. Hope, P.I. Spantidea, C.H. Kiernan, et al (Frontiers in Immunology, 2019).

The study

• Authors: J.L. Hope, P.I. Spantidea, C.H. Kiernan, C.J. Stairiker, L.C. Rijsbergen, M. van Meurs, I. Brouwers-Haspels, Y.M. Mueller, D.J. Nelson, L.M. Bradley, J.G.J.V. Aerts, P.D. Katsikis
• Journal: Frontiers in Immunology
• Published: 2019;10:3074
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The immune system, and in particular, cytotoxic CD8+ T cells (CTLs), plays a vital part in the prevention and elimination of tumors. In many patients, however, CTL-mediated tumor killing ultimately fails in the clearance of cancer cells resulting in disease progression, in large part due to the progression of effector CTL into exhausted CTL. While there have been major breakthroughs in the development of CTL-mediated "reinvigoration"-driven immunotherapies such as checkpoint blockade therapy, there remains a need to better understand the drivers behind the development of T cell exhaustion. Our study highlights the unique differences in T cell exhaustion development in tumor-specific CTL which arises over time in a mouse model of mesothelioma. Importantly, we also show that peripheral tumor-specific T cells have a unique expression profile compared to exhausted tumor-infiltrating CTL at a late-stage of tumor progression in mice. Together, these data suggest that greater emphasis should be placed on understanding contributions of individual microenvironments in the development of T cell exhaustion.

Copyright © 2020 Hope, Spantidea, Kiernan, Stairiker, Rijsbergen, van Meurs, Brouwers-Haspels, Mueller, Nelson, Bradley, Aerts and Katsikis.

In plain English

This was a laboratory experiment in mice using the AE17sOVA mesothelioma tumor line (AE17 was originally generated by injecting asbestos fibers into the peritoneum of C57BL/6 mice and was then transfected with secretory ovalbumin). Adult female C57BL/6 mice received 1 x 10(4) naive OT-I CD45.1+ CD8+ T cells intravenously and, 3 hours later, 5 x 10(5) AE17sOVA cells under the skin of the hind flank; tumors, draining and non-draining lymph nodes and spleens were analyzed by flow cytometry at days 15 and 22, with influenza (WSN-OVA) infected mice used for comparison. Inside tumors, donor T cells fell from 87.97% of CD8+ T cells at day 15 to 11.72% at day 22 (p < 0.001), Ki-67 expression fell from 96.26 ± 1.5% to 48.44 ± 20.29% (p < 0.001), and cells co-producing IFN-gamma and TNF-alpha fell from 30.72 ± 11.52% to 12.65 ± 10.96% (p = 0.0132), with increased co-expression of inhibitory receptors. The authors concluded that exhaustion followed a gradient depending on tissue location.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (mouse tumor model with adoptive T cell transfer and flow cytometry)
• Who was studied: Adult (8-10 week old) female C57BL/6 mice bearing subcutaneous AE17sOVA mesothelioma tumors, analyzed at day 15 (n = 4-5) and day 22 (n = 11-12), with WSN-OVA influenza-infected mice (n = 3-4) for comparison; work done at Erasmus MC (Rotterdam) and Sanford Burnham Prebys (La Jolla)
• Exposure: Not an asbestos exposure study in animals or people: the AE17 mesothelioma cell line used had originally been produced by intraperitoneal injection of asbestos fibers into C57BL/6 mice; the experimental exposure here was injection of 5 x 10(5) AE17sOVA tumor cells plus adoptively transferred OVA-specific OT-I CD8+ T cells
• Main results:
  • Tumor-infiltrating donor OT-I T cells fell as a proportion of CD8+ T cells between day 15 and day 22
  • Proliferation marker Ki-67 in intratumoral donor OT-I T cells was lower at day 22 than day 15
  • Polyfunctional (IFN-gamma plus TNF-alpha) cytokine production by intratumoral donor OT-I T cells was reduced at day 22 compared with day 15
  • Intratumoral donor OT-I T cells at day 22 co-expressed more inhibitory receptors (PD-1, LAG3, 2B4, CD160) than at day 15
  • At day 22, donor OT-I T cells in the spleen kept more Ki-67 expression than those in the tumor
  • At day 22, splenic donor OT-I T cells produced more cytokine than matched intratumoral cells, and more were polyfunctional
  • Clustering analysis placed draining lymph node cells between spleen and tumor cells
  • Eomes was not increased in day 22 intratumoral donor cells relative to spleen and draining lymph node
• The authors' conclusion: The authors concluded that the degree of CD8+ T cell exhaustion depended on the tissue microenvironment from which the cells were isolated, forming a gradient from tumor to draining lymph node to spleen, and that the AE17sOVA model is suitable for studying the timing and location of anti-tumor interventions
• Limitations the authors state:
  • The authors noted that inhibitory receptor expression seen in influenza-infected lungs at day 15 was not accompanied by functional or proliferative defects and needs further study
  • The authors' explanation based on differing tumor antigen levels between tissues was stated as likely, not measured in this study
  • Loss of OVA antigen in large tumors was referred to as unpublished data and belief, not shown here
  • Findings for endogenous OVA-specific CTL were not shown

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Disease Progression.

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