High density and proximity of CD8+ T cells to tumor cells are correlated with better response to nivolumab treatment in metastatic pleural mesothelioma

Our plain-English summary of High density and proximity of CD8+ T cells to tumor cells are correlated with better response to nivolumab treatment in metastatic pleural mesothelioma, by Y. Yin, R. Sakakibara, T. Honda, et al (Thoracic Cancer, 2023).

The study

• Authors: Y. Yin, R. Sakakibara, T. Honda, S. Kirimura, P. Daroonpan, M. Kobayashi, K. Ando, H. Ujiie, T. Kato, K. Kaga, T. Mitsumura, R. Nakano, H. Sakashita, S. Matsuge, H. Ishibashi, T. Akashi, Y. Hida, T. Morohoshi, M. Azuma, K. Okubo, Y. Miyazaki
• Journal: Thoracic Cancer
• Published: 2023;14(20):1991-2000
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer.

Methods: A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD-L1 positive cells, cell density, and cell-to-cell distance were analyzed by multiplex immunofluorescence.

Results: PD-L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group.

Conclusions: High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma.

© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

In plain English

This retrospective study from four hospitals in Japan looked at 22 people with pleural mesothelioma that had come back after surgery and who were then treated with the immunotherapy drug nivolumab between August 2016 and October 2021. Using tissue removed at their earlier surgery, the authors stained and counted immune cells (T cells) and tumor cells and measured the distances between them. Four patients responded to nivolumab and 18 did not. Sixteen of the 22 (73%) had asbestos exposure. Fiber types were not reported, and asbestos exposure did not differ significantly between the two groups. PD-L1, a tumor marker, did not differ significantly between groups. In the central tumor, responders had higher densities of total T cells (711.3 vs 252.7 cells per square millimeter) and of CD8+ T cells (637.8 vs 161.4). In responders, CD8+ T cells sat closer to tumor cells (39.4 vs 104.6 micrometers), while regulatory T cells sat farther away (221.0 vs 164.8 micrometers). The authors concluded that these patterns were associated with better response. They noted that only four patients were in the response group and that a larger validation cohort is needed.

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: retrospective multicenter study of surgical tissue specimens, analyzed with multiplex immunofluorescence
• Who was studied: 22 patients with pleural mesothelioma who relapsed after surgery and were treated with nivolumab between August 2016 and October 2021 at four hospitals in Japan. 21 were male; 21 had epithelioid and 1 biphasic histology. Samples came from first-line surgery, not from just before nivolumab.
• Exposure: Treatment with nivolumab (an immune checkpoint inhibitor). Asbestos exposure was recorded in 16 of 22 patients (73%), never in 4 (18%) and not evaluated in 2 (9%). No fiber types or doses were given.
• Main results:
  • 4 patients were in the response group (complete or partial response) and 18 in the nonresponse group (stable or progressive disease)
  • There was no significant difference in asbestos exposure, smoking history or histology between the response and nonresponse groups
  • The response group was significantly younger than the nonresponse group (median age 50 vs 68 years, p = 0.005)
  • PD-L1 was positive in all 22 samples. Mean tumor proportion score was 11% in the response group and 17% in the nonresponse group, with no significant difference.
  • In the central tumor, density was higher in the response group than in the nonresponse group for total T cells (711.3 vs 252.7 cells/mm2, p < 0.05) and for CD8+ T cells (637.8 vs 161.4 cells/mm2, p < 0.01). There were no significant differences in the invasive margin.
  • In the central tumor of the response group compared with the nonresponse group, CD8+ T cells were more clustered (24.8 vs 61.2 micrometers, p < 0.05) and closer to tumor cells (39.4 vs 104.6 micrometers, p < 0.05)
  • Regulatory T cells were farther from tumor cells in the central tumor of the response group than of the nonresponse group (221.0 vs 164.8 micrometers, p < 0.05)
  • A closer CD8 cluster was significantly correlated with better progression-free survival (p = 0.038). In multivariate analysis, CD8 cluster (above vs below average) had a hazard ratio of 7.884 (95% CI 1.366 to 45.490, p = 0.021).
• The authors' conclusion: The authors concluded that high density and proximity of CD8+ T cells, and a greater distance between regulatory T cells and tumor cells, were associated with a better response to nivolumab. They suggested that analysis of the tumor microenvironment may help predict immunotherapy efficacy in pleural mesothelioma.
• Limitations the authors state:
  • The sample size was small, with only four patients in the response group; a larger validation cohort is needed
  • Only surgical specimens were included, with no biopsy specimens
  • The absence of patients who received chemotherapy may have been a confounding factor
  • Staining covered only a subset of immune cell types; B cells, natural killer cells and macrophages were not examined
  • The study was retrospective; prospective research is needed to validate the findings

Topics

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

Medical terms in this study, explained in our Lexicon: Nivolumab (Opdivo), Pleural Mesothelioma, checkpoint inhibitors, Tumor Microenvironment, PD-L1.

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