Antipodoplanin antibody enhances the antitumor effects of CTLA-4 blockade against malignant mesothelioma by natural killer cells

Our plain-English summary of Antipodoplanin antibody enhances the antitumor effects of CTLA-4 blockade against malignant mesothelioma by natural killer cells, by H. Yoneda, A. Mitsuhashi, A. Yoshida, et al (Cancer Science, 2024).

The study

• Authors: H. Yoneda, A. Mitsuhashi, A. Yoshida, H. Ogino, S. Itakura, N.T. Nguyen, H. Nokihara, S. Sato, T. Shinohara, M. Hanibuchi, S. Abe, M.K. Kaneko, Y. Kato, Y. Nishioka
• Journal: Cancer Science
• Published: 2024;115(2):357-368
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Combination immunotherapy with multiple immune checkpoint inhibitors (ICIs) has been approved for various types of malignancies, including malignant pleural mesothelioma (MPM). Podoplanin (PDPN), a transmembrane sialomucin-like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN-targeting Ab reagent with high Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, the effects of anti-PDPN Abs on various tumor-infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat-mouse chimeric anti-mouse PDPN IgG2a mAb (PMab-1-mG2a ) and its core-fucose-deficient Ab (PMab-1-mG2a -f) to address these limitations. We identified the ADCC and CDC activity of PMab-1-mG2a -f against the PDPN-expressing mesothelioma cell line AB1-HA. The antitumor effect of monotherapy with PMab-1-mG2a -f was not sufficient to overcome tumor progression in AB1-HA-bearing immunocompetent mice. However, PMab-1-mG2a -f enhanced the antitumor effects of CTLA-4 blockade. Combination therapy with anti-PDPN Ab and anti-CTLA-4 Ab increased tumor-infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab-1-mG2a -f and CTLA-4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM.

© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory and animal study in which the authors made a new rat–mouse chimeric anti-mouse podoplanin (PDPN) IgG2a antibody (PMab-1-mG2a) and a core-fucose-deficient version (PMab-1-mG2a-f), and tested them against the mouse malignant mesothelioma cell line AB1-HA. Flow cytometry showed high PDPN on the cell surface of AB1-HA, the colon cancer line MC38 and the melanoma line B16. In chromium-release assays, PMab-1-mG2a showed no mouse splenocyte-dependent antibody-dependent cellular cytotoxicity (ADCC) but high complement-dependent cytotoxicity, while the core-fucose-deficient PMab-1-mG2a-f added ADCC activity; both were extremely weak against PDPN-negative LLC cells. In AB1-HA-bearing BALB/c mice, 50 micrograms of PMab-1-mG2a-f only tended to suppress tumour growth, and 100 or 500 micrograms failed. Combining PMab-1-mG2a-f with anti-CTLA-4 antibody significantly suppressed tumour growth and further increased tumour-infiltrating natural killer (NK) cells, whereas PMab-1-mG2a-f did not reinforce the antitumour effects of anti-PD-1 antibody. Depleting NK cells with an anti-IL-2R-beta antibody inhibited the combination's antitumour effect, although that antibody also reduced tumour-infiltrating regulatory T cells. The authors concluded that NK cells play a pivotal role in this combination immunotherapy targeting PDPN.

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: Preclinical laboratory and animal experiment (in vitro cytotoxicity assays plus syngeneic mouse tumour models)
• Who was studied: Mouse tumour cell lines (mesothelioma AB1-HA and AC29, lung cancer LLC, melanoma B16, fibrosarcoma MCA205, colon carcinoma MC38) and six-week-old male BALB/c, C57BL/6J and C.B-17 SCID mice; work carried out at Tokushima University, Japan
• Exposure: Rat-mouse chimeric anti-mouse podoplanin IgG2a antibody PMab-1-mG2a and its core-fucose-deficient form PMab-1-mG2a-f (50, 100 or 500 micrograms per mouse), given alone or with anti-CTLA-4 antibody (5 micrograms per mouse) or anti-PD-1 antibody; NK cells depleted with anti-IL-2R-beta antibody, T cells with anti-CD4 or anti-CD8 antibodies
• Main results:
  • High surface PDPN was detected on the mesothelioma line AB1-HA, the colon cancer line MC38 and the melanoma line B16
  • Against AB1-HA, PMab-1-mG2a showed no splenocyte-dependent ADCC but high CDC, while the core-fucose-deficient PMab-1-mG2a-f added ADCC activity
  • Both antibodies had extremely weak ADCC and CDC against the PDPN-negative line LLC, and PMab-1-mG2a-f (50 micrograms) did not act against LLC tumours in vivo
  • In AB1-HA-bearing BALB/c mice, monotherapy at 50 micrograms only tended to suppress tumour growth, and 100 or 500 micrograms showed no antitumour effect
  • Monotherapy slightly increased tumour-infiltrating NKp46+ NK cells without accumulation of CD8+ or CD4+ T cells
  • Combination of anti-PDPN antibody with anti-CTLA-4 antibody significantly suppressed tumour progression, whereas PMab-1-mG2a-f did not reinforce the antitumour effects of anti-PD-1 antibody
  • The anti-PDPN plus anti-CTLA-4 combination further increased tumour-infiltrating NK and NKT cells but not CD8 or CD4 T cells
  • Pretreatment with the anti-IL-2R-beta antibody TM-beta-1 inhibited the antitumour effect of the combination, while depleting CD4 or CD8 T cells did not; TM-beta-1 also decreased tumour-infiltrating regulatory T cells
  • By flow cytometry, some tumour-infiltrating NK cells and macrophages expressed CTLA-4 while most T cells did not; PD-1 was seen on various immune cells, especially CD4+ T cells
• The authors' conclusion: The authors concluded that they found synergistic antitumour effects of anti-PDPN and anti-CTLA-4 antibodies that depended on NK cells, and that this points to a possible therapeutic strategy for unresectable malignant pleural mesothelioma
• Limitations the authors state:
  • The effect of anti-human PDPN antibodies against human mesothelioma under immunocompetent conditions was not addressed; the authors state a humanized chimera mouse model would be needed
  • The combination might influence regulatory T cells; the authors used a CTLA-4 clone reported to lack ADCC activity on Tregs
  • The mechanism by which ADCC activity enhances NK cell accumulation was not determined

Topics

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

Medical terms in this study, explained in our Lexicon: CTLA-4, Mesothelioma, Immunotherapy, checkpoint inhibitors, Pleural Mesothelioma, Podoplanin (D2-40), Glycoprotein, Synergistic Effect.

Related studies

• Cancer-Specific Antihuman Podoplanin Antibody chLpMab-2f Exerts Antitumor Effects Against Pleural Mesothelioma — A. Yoshida, S. Abe, et al. (2026)
• Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model — S. Abe, M.K. Kaneko, et al. (2016)
• Antitumor activity of chLpMab-2, a human-mouse chimeric cancer-specific antihuman podoplanin antibody, via antibody-dependent cellular cytotoxicity — M.K. Kaneko, S. Yamada, et al. (2017)
• Epitope Mapping of Monoclonal Antibody PMab-233 Against Tasmanian Devil Podoplanin — M. Sano, M.K. Kaneko, et al. (2019)
• SS1P Immunotoxin Induces Markers of Immunogenic Cell Death and Enhances the Effect of the CTLA-4 Blockade in AE17M Mouse Mesothelioma Tumors — Y. Leshem, E.M. King, et al. (2018)
• S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor — N.T. Nguyen, A. Mitsuhashi, et al. (2023)

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