Next Article in Journal
Cannabinoid Receptor Type-2 in B Cells Is Associated with Tumor Immunity in Melanoma
Next Article in Special Issue
The Soluble Factor from Oral Cancer Cell Lines Inhibits Interferon-γ Production by OK-432 via the CD40/CD40 Ligand Pathway
Previous Article in Journal
Iatrogenic Ocular Surface Diseases Occurring during and/or after Different Treatments for Ocular Tumours
Previous Article in Special Issue
CD137+ T-Cells: Protagonists of the Immunotherapy Revolution
Article

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

1
Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 252 50 Vestec, Czech Republic
2
Department of Cell Biology, Faculty of Science, Charles University, BIOCEV, 252 50 Vestec, Czech Republic
*
Author to whom correspondence should be addressed.
Academic Editor: Peter Kern
Cancers 2021, 13(8), 1935; https://doi.org/10.3390/cancers13081935
Received: 18 March 2021 / Revised: 7 April 2021 / Accepted: 14 April 2021 / Published: 16 April 2021
(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)
The recent discovery of immune checkpoint inhibitors constituted a breakthrough in cancer treatment, but most patients are resistant to this therapy. Although the co-stimulatory molecule cluster of differentiation (CD) 80 has been detected in several types of tumor cells, its role in the tumor microenvironment and its sensitivity to immune checkpoint blockade are unclear. We, therefore, introduced a clinically relevant mouse tumor model with deactivated CD80. The deactivation promoted a “hot” tumor microenvironment and enhanced the sensitivity to immune checkpoint blockade with antibody against the cytotoxic T-lymphocyte antigen 4 (CTLA-4). This study contributed to the research into predictive markers to select patients who are suitable for immune checkpoint blockade therapy and suggested the development of a novel cancer immunotherapy based on a tumor-cell-targeted CD80 blockade.
Cluster of differentiation (CD) 80 is mainly expressed in immune cells but can also be found in several types of cancer cells. This molecule may either activate or inhibit immune reactions. Here, we determined the immunosuppressive role of CD80 in the tumor microenvironment by CRISPR/Cas9-mediated deactivation of the corresponding gene in the mouse oncogenic TC-1 cell line. The tumor cells with deactivated CD80 (TC-1/dCD80-1) were more immunogenic than parental cells and induced tumors that gained sensitivity to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, as compared with the TC-1 cells. In vivo depletion experiments showed that the deactivation of CD80 switched the pro-tumorigenic effect of macrophages observed in TC-1-induced tumors into an anti-tumorigenic effect in TC-1/dCD80-1 tumors and induced the pro-tumorigenic activity of CD4+ cells. Moreover, the frequency of lymphoid and myeloid cells and the CTLA-4 expression by T helper (Th)17 cells were increased in TC-1/dCD80-1- compared with that in the TC-1-induced tumors. CTLA-4 blockade downregulated the frequencies of most immune cell types and upregulated the frequency of M2 macrophages in the TC-1 tumors, while it increased the frequency of lymphoid cells in TC-1/dCD80-1-induced tumors. Furthermore, the anti-CTLA-4 therapy enhanced the frequency of CD8+ T cells as well as CD4+ T cells, especially for a Th1 subset. Regulatory T cells (Treg) formed the most abundant CD4+ T cell subset in untreated tumors. The anti-CTLA-4 treatment downregulated the frequency of Treg cells with limited immunosuppressive potential in the TC-1 tumors, whereas it enriched this type of Treg cells and decreased the Treg cells with high immunosuppressive potential in TC-1/dCD80-1-induced tumors. The immunosuppressive role of tumor-cell-expressed CD80 should be considered in research into biomarkers for the prediction of cancer patients’ sensitivity to immune checkpoint inhibitors and for the development of a tumor-cell-specific CD80 blockade. View Full-Text
Keywords: CD80; CTLA-4; PD-L1; tumor-infiltrating lymphocytes; cancer; immune checkpoint blockade CD80; CTLA-4; PD-L1; tumor-infiltrating lymphocytes; cancer; immune checkpoint blockade
Show Figures

Graphical abstract

MDPI and ACS Style

Vackova, J.; Polakova, I.; Johari, S.D.; Smahel, M. CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade. Cancers 2021, 13, 1935. https://doi.org/10.3390/cancers13081935

AMA Style

Vackova J, Polakova I, Johari SD, Smahel M. CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade. Cancers. 2021; 13(8):1935. https://doi.org/10.3390/cancers13081935

Chicago/Turabian Style

Vackova, Julie, Ingrid Polakova, Shweta D. Johari, and Michal Smahel. 2021. "CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade" Cancers 13, no. 8: 1935. https://doi.org/10.3390/cancers13081935

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop