Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells

Our plain-English summary of Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells, by Z. Yu, Z. Tan, B.K. Lee, et al (Oncotarget, 2015).

The study

• Authors: Z. Yu, Z. Tan, B.K. Lee, J. Tang, X. Wu, K.W. Cheung, N.T. Lo, K. Man, L. Liu, Z. Chen
• Journal: Oncotarget
• Published: 2015;6(32):32426-38
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

A key focus in cancer immunotherapy is to investigate the mechanism of efficacious vaccine responses. Using HIV-1 GAG-p24 in a model PD1-based DNA vaccine, we recently reported that vaccine-elicited CD8+ T cells conferred complete prevention and therapeutic cure of AB1-GAG malignant mesothelioma in immunocompetent BALB/c mice. Here, we further investigated the efficacy and correlation of protection on the model vaccine-mediated antigen spreading against wild-type AB1 (WT-AB1) mesothelioma. We found that this vaccine was able to protect mice completely from three consecutive lethal challenges of AB1-GAG mesothelioma. Through antigen spreading these animals also developed tumor-specific cytotoxic CD8+ T cells, but neither CD4+ T cells nor antibodies, rejecting WT-AB1 mesothelioma. A majority of these protected mice (90%) were also completely protected against the lethal WT-AB1 challenge. Adoptive cell transfer experiments further demonstrated that antigen spreading-induced CD8+ T cells conferred efficacious therapeutic effects against established WT-AB1 mesothelioma and prevented the increase of exhausted PD-1+ and Tim-3+ CD8+ T cells. A significant inverse correlation was found between the frequency of functional PD1-Tim3- CD8+ T cells and that of MDSCs or tumor mass in vivo. Mechanistically, we found that WT-AB1 mesothelioma induced predominantly polymorphonuclear (PMN) MDSCs in vivo. In co-cultures with efficacious CD8+ T cells, a significant number of PMN-MDSCs underwent apoptosis in a dose-dependent way. Our findings indicate that efficacious CD8+ T cells capable of eliminating both tumor cells and MDSCs are likely necessary for fighting wild-type malignant mesothelioma.

In plain English

This was a laboratory experiment in mice using the AB1 murine malignant mesothelioma cell line. BALB/c mice were immunized three times with the PD1-based DNA vaccine sPD1-p24fc (or p24fc or PBS) with electroporation, then given three consecutive subcutaneous challenges of 5x10^5 AB1-GAG mesothelioma cells (cells engineered to express HIV-1 GAG). All sPD1-p24fc vaccinated mice cleared the implanted AB1-GAG cells and survived, while control animals died within 4-6 weeks; imaging showed significantly suppressed tumour growth (P = 0.007). These protected mice developed antibodies binding wild-type AB1 (WT-AB1) cells, but in the ADCC assay the sera from the three groups showed no significant difference, and purified CD8+ T cells, but not CD4+ T cells, killed WT-AB1 cells in vitro (P = 0.00078). When challenged with a lethal dose of WT-AB1, 9 of 10 (90%) of these mice stayed tumour-free, while all controls died within 40 days (P = 0.0002). Transferring their CD8+ T cells into SCID mice with established WT-AB1 tumours reduced tumour growth (P = 0.0194). AB1-bearing mice had predominantly PMN-MDSCs (over 80% of total MDSCs), which underwent apoptosis in co-culture with these CD8+ T 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: Animal (mouse) experiment: prophylactic vaccination and tumour challenge studies plus adoptive cell transfer and in vitro co-culture assays
• Who was studied: 5- to 8-week-old female BALB/c mice and C.B-17/Icr-scid (SCID) mice, maintained at the University of Hong Kong laboratory animal unit; groups of 5 to 10 mice per experiment
• Exposure: Intramuscular DNA vaccination with 100 micrograms of sPD1-p24fc, p24fc, or PBS control, with electroporation, followed by subcutaneous challenges with 5x10^5 AB1-GAG and then wild-type AB1 mesothelioma cells
• Main results:
  • All sPD1-p24fc/EP vaccinated mice cleared the AB1-GAG implants and survived three consecutive challenges, with significantly suppressed tumour growth (P = 0.007); no control animal survived even one challenge, dying within 4-6 weeks
  • CD8+ T cells from the protected (group I) mice killed WT-AB1 cells in vitro at effector-to-target ratios of 10:1 and 20:1 (P = 0.00078), whereas CD4+ T cells showed no significant cytotoxicity
  • After lethal WT-AB1 challenge, 9 of 10 (90%) group I mice remained tumour-free; all control mice developed tumours and died within 40 days (P = 0.0002), with tumour growth differing at P = 0.0098
  • Adoptive transfer of 2x10^6 CD8+ T cells from group I mice into SCID mice with 7-day established WT-AB1 tumours significantly reduced tumour (P = 0.0194); CD8+ T cells from vaccinated-only (group II) mice gave no protection
  • In SCID recipients, group I' mice had lower PD1 (P = 0.0058) and Tim3 (P = 0.0028) expression on CD8+ T cells and reduced MDSC frequency (P = 0.0303)
  • The frequency of PD1-Tim3- CD8+ T cells was inversely correlated with MDSC frequency (P = 0.0001) and with tumour mass (P less than 0.0001)
  • In AB1-bearing BALB/c mice, PMN-MDSCs (CD11b+Ly6G+Ly6Clow/int) made up over 80% of total splenic MDSCs; co-culture with protective CD8+ T cells caused dose-dependent PMN-MDSC apoptosis
  • Anti-sera from the protected mice bound WT-AB1 cells, but in the ADCC assay sera from the three groups showed no significant difference, and the authors stated these sera may not mediate ADCC; transferred anti-sera did not eliminate WT-AB1 tumours in SCID mice
• The authors' conclusion: The authors concluded that CD8+ T cells induced through vaccine-mediated antigen spreading are tumour-specific, protect against lethal wild-type mesothelioma challenge, and that CD8+ T cells able to eliminate both tumour cells and MDSCs are likely needed for effective immunotherapy of malignant mesothelioma
• Limitations the authors state:
  • The authors stated that the tumour antigens responsible for eliciting the efficacious CD8+ T cells remain unknown, so the frequency and functionality of those cells could not be measured

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: Mesothelioma, Immunotherapy, Apoptosis.

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