Immunostimulatory oncolytic activity of coxsackievirus A11 in human malignant pleural mesothelioma

Our plain-English summary of Immunostimulatory oncolytic activity of coxsackievirus A11 in human malignant pleural mesothelioma, by K. Okamura, H. Inoue, K. Tanaka, et al (Cancer Science, 2023).

The study

• Authors: K. Okamura, H. Inoue, K. Tanaka, Y. Ikematsu, R. Furukawa, K. Ota, Y. Yoneshima, E. Iwama, I. Okamoto
• Journal: Cancer Science
• Published: 2023;114(3):1095-1107
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive solid cancer with a poor prognosis, whereas coxsackievirus A11 (CVA11) is a potential oncolytic virus for cancer treatment. We here investigated the oncolytic activity of CVA11 with human MPM cell lines. CVA11 infection was cytotoxic in all six MPM cell lines examined and showed no or minimal cytotoxicity toward normal human normal cell lines. MPM cells with a higher surface level of intercellular adhesion molecule-1 (ICAM-1) expression tended to be more susceptible to CVA11-induced cytotoxicity, and a neutralizing antibody to ICAM-1 attenuated such cytotoxicity. CVA11 infection activated signaling by Akt and extracellular signal-regulated kinase (ERK) pathways, and inhibitors of such signaling also abrogated CVA11-mediated cytotoxicity. Furthermore, CVA11 infection-triggered multiple modes of tumor cell death including apoptosis, pyroptosis, and necroptosis, and such death was accompanied by the release or exposure of the proinflammatory cytokine interleukin-1β and damage-associated molecular patterns such as calreticulin, high-mobility group box-1, annexin A1, and heat shock protein 70, which are hallmarks of immunogenic cell death. Notably, in vivo treatment of human MPM xenografts with intratumoral CVA11 injection resulted in significant suppression of tumor growth in SCID mice, and all mice infected with CVA11 showed no significant change in body weight. Our findings collectively suggest that the oncolytic activity of CVA11 for MPM is dependent on ICAM-1 as a virus receptor, as well as on Akt and ERK signaling, and that oncolytic virotherapy with CVA11 is a promising treatment modality with immunostimulatory activity for human MPM.

© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

In plain English

This was a laboratory study of coxsackievirus A11 (CVA11, prototype Belgium-1 strain) as an oncolytic virus against human malignant pleural mesothelioma (MPM), using cultured cell lines and mouse xenografts. The authors infected six human MPM cell lines, a normal human mesothelial line (MeT-5A) and a normal keratinocyte line (HaCaT) at multiplicities of infection of 0.1, 1 or 10. CVA11 killed all six MPM lines in an MOI-dependent way, with less cytotoxicity in MeT-5A and none in HaCaT cells. Cell lines with higher surface ICAM-1 tended to be more susceptible, and neutralizing antibodies to ICAM-1 attenuated the killing. Infection induced ERK and Akt phosphorylation in the four MPM lines examined, and in H2052 cells a MEK inhibitor and a PI3K inhibitor each reduced cytotoxicity and the released viral titer. The authors reported apoptosis, pyroptosis and necroptosis, release of IL-1beta, surface calreticulin exposure, release of HMGB1, annexin A1 and HSP70, and increased surface PD-L1. In SCID mice, five intratumoral CVA11 injections significantly reduced H2052 tumor volume at day 54 (p less than 0.001), with complete regression in four of five treated mice and no significant weight loss. No asbestos exposure was studied.

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 study using human cell lines plus a mouse xenograft experiment (preclinical oncolytic virus study)
• Who was studied: Six human malignant pleural mesothelioma cell lines (H2052, H2452, MSTO, ACC-MESO-1, ACC-MESO-4, HMMME), normal human cell lines MeT-5A and HaCaT, and four-week-old female CB-17/Icr-scid/scidJcl mice (n = 10) bearing subcutaneous H2052 xenografts; Kyushu University, Japan
• Exposure: Infection with coxsackievirus A11 (prototype Belgium-1 strain) in vitro at MOI 0.1, 1 or 10, and five serial intratumoral injections of 2 x 10^6 TCID50 every 2 days in mice; inhibitors and anti-ICAM-1 antibody used in some experiments
• Main results:
  • CVA11 was cytotoxic in all six MPM cell lines in an MOI-dependent manner, with less cytotoxicity in MeT-5A cells and none in HaCaT cells
  • In the MPM cell lines, higher surface ICAM-1 tended to accompany greater CVA11 cytotoxicity, and anti-ICAM-1 neutralizing antibodies reduced the killing in all six lines
  • Surface expression quantified by flow cytometry for the four lines in Table 1: ICAM-1 97.5% (H2052), 100% (H2452), 19.3% (MESO-1), 48.0% (MSTO); DAF 99.0%, 71.0%, 98.6%, 99.7% respectively
  • CVA11 infection induced phosphorylation of ERK and Akt in all four MPM cell lines examined
  • In H2052 cells only, the MEK inhibitor PD0325901 and the PI3K inhibitor LY294002 inhibited CVA11 cytotoxicity and reduced the released viral titer at 36 h post-infection
  • Of the caspase inhibitors tested in H2052 cells, only the caspase-1 inhibitor Ac-YVAD-CMK attenuated cytotoxicity and reduced released viral titer; necrostatin-1 (RIPK1 inhibitor) also attenuated cytotoxicity, and MLKL phosphorylation was induced
  • CVA11 infection induced surface calreticulin exposure and MOI-dependent release of HMGB1, annexin A1 and HSP70 from the five MPM cell lines examined, and increased IL-1beta in supernatants
  • Surface PD-L1, but not PD-L2, increased after CVA11 infection in H2052, H2452 and MESO-4 cells
  • In the xenograft experiment, CVA11-treated mice had significant tumor regression at day 54 versus untreated mice (p < 0.001), with complete regression in four of five treated mice and none of the untreated mice; no significant weight loss in treated mice
• The authors' conclusion: The authors concluded that CVA11's oncolytic activity for MPM depends on ICAM-1 as a virus receptor and on Akt and ERK signaling, and that CVA11 virotherapy is a promising treatment modality with immunostimulatory activity for human MPM
• Limitations the authors state:
  • The authors stated that further preclinical studies, including biochemical and pathological analyses in mice and nonhuman primates, are needed to confirm the safety of CVA11

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Apoptosis, Cytokine.

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