Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors

Our plain-English summary of Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors, by M.M. Awad, R.E. Jones, H. Liu, et al (Cancer Immunology Research, 2016).

The study

• Authors: M.M. Awad, R.E. Jones, H. Liu, P.H. Lizotte, E.V. Ivanova, M. Kulkarni, G.S. Herter-Sprie, X. Liao, A.A. Santos, M.A. Bittinger, L. Keogh, S. Koyama, C. Almonte, J.M. English, J. Barlow, W.G. Richards, D.A. Barbie, A.J. Bass, S.J. Rodig, F.S. Hodi, K.W. Wucherpfennig, P.A. Jänne, L.M. Sholl, P.S. Hammerman, K.K. Wong, R. Bueno
• Journal: Cancer Immunology Research
• Published: 2016;4(12):1038-1048
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens. Compared with PD-L1-negative tumors, PD-L1-positive tumors had significantly more infiltrating CD45+ immune cells, a significantly higher proportion of infiltrating CD3+ T cells, and a significantly higher percentage of CD3+ cells displaying the activated HLA-DR+/CD38+ phenotype. PD-L1-positive tumors also had a significantly higher proportion of proliferating CD8+ T cells, a higher fraction of FOXP3+/CD4+ Tregs, and increased expression of PD-1 and TIM-3 on CD4+ and CD8+ T cells. Double-positive PD-1+/TIM-3+ CD8+ T cells were more commonly found on PD-L1-positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3+ T cells and PD-1+/TIM-3+ CD8+ T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. Cancer Immunol Res; 4(12); 1038-48. ©2016 AACR.

©2016 American Association for Cancer Research.

In plain English

This laboratory study examined tumor tissue removed during surgery from 43 consecutive patients with malignant pleural mesothelioma at Brigham and Women's Hospital and the Dana-Farber Cancer Institute in Boston. The authors developed a flow cytometry method to count and characterize immune cells in tumors. They also tested the tumors for PD-L1, a protein involved in the pathway targeted by PD-1 inhibitor drugs. The study did not examine asbestos exposure. Of 39 tumors tested, 18 were PD-L1 positive. Sarcomatoid or biphasic tumors were more often positive (10 of 13) than epithelioid tumors (8 of 26). Compared with PD-L1-negative tumors, PD-L1-positive tumors contained more T cells (median 30.4% versus 19.3% of immune cells), more regulatory T cells, and more T cells carrying the inhibitory markers PD-1 and TIM-3. Overall survival did not differ significantly by PD-L1 status. The authors concluded that the frequent presence of both PD-1 and TIM-3 suggested combined blocking of both pathways might be an effective strategy in mesothelioma. They noted that flow cytometry loses the spatial relationship between tumor and immune cells.

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: Laboratory analysis of surgically resected human tumor specimens (immune cell profiling by flow cytometry, with immunohistochemistry), with a survival analysis
• Who was studied: 43 consecutive resected malignant pleural mesothelioma specimens from patients undergoing surgery at Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston. The specimens were 29 epithelioid, 4 sarcomatoid and 10 biphasic. 33 patients were male and 42 were White. Paired normal tissue was analyzed in 7 cases.
• Exposure: Asbestos exposure was not studied. The factors compared were tumor PD-L1 status, histologic subtype and tumor gene mutations (BAP1, NF2).
• Main results:
  • Of 39 tumors with enough tissue for PD-L1 testing, 18 (46%) were PD-L1 positive and 21 (54%) were PD-L1 negative.
  • Nonepithelioid (sarcomatoid and biphasic) tumors were more likely to be PD-L1 positive (10/13, 77%) than epithelioid tumors (8/26, 31%), P = 0.01.
  • PD-L1-positive tumors had a higher percentage of CD45+ immune cells among live cells (median 87.7%) than PD-L1-negative tumors (median 68.2%), P = 0.05, which the authors described as significant.
  • By flow cytometry, PD-L1-positive tumors had more CD3+ T cells than PD-L1-negative tumors (median 30.4% vs 19.3% of CD45+ cells, P less than 0.05).
  • By immunohistochemistry, PD-L1-positive tumors also had more infiltrating T cells than PD-L1-negative tumors (median 176 vs 59 cells per high-power field, P = 0.006).
  • CD4+ T cells in PD-L1-positive tumors were more likely to express the regulatory T-cell marker FOXP3 (P = 0.005).
  • CD8+ T cells in PD-L1-positive tumors were more likely to express the inhibitory markers TIM-3 (P = 0.003) and PD-1 (P = 0.008).
  • Most PD-L1-negative tumors had BAP1 mutations (11/12), compared with roughly half of PD-L1-positive tumors (7/15), P = 0.02.
  • There was no significant difference in overall survival between patients with PD-L1-positive and PD-L1-negative tumors (P = 0.15).
  • Patients with nonepithelioid mesothelioma had a significantly worse prognosis than patients with epithelioid tumors (P = 0.02).
• The authors' conclusion: The authors concluded that the frequent coexpression of PD-1 and TIM-3 on CD8+ T cells suggests that combined inhibition of the PD-1 and TIM-3 pathways might be an effective therapeutic strategy in mesothelioma.
• Limitations the authors state:
  • Germline DNA was not available, so the authors could not tell whether tumor mutations were inherited (germline) or acquired (somatic).
  • Flow cytometry loses the spatial relationships between tumor cells and immune cells.

Topics

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

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Mesothelioma, Immunohistochemistry, Epithelioid, Sarcomatoid, Biphasic Mesothelioma, Mesothelioma, Histological Subtype.

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