Cervical cancer cells suppress effector functions of cytotoxic T cells through the adenosinergic pathway

Mora‐García, María de Lourdes; Ávila-Ibarra, Luis Roberto; García‐Rocha, Rosario; Weiss‐Steider, Benny; Hernández‐Montes, Jorge; Don‐López, Christian Azucena; Gutiérrez-Serrano, Vianey; Titla-Vilchis, I.J.; Fuentes-Castañeda, M.C.; Monroy-Mora, Alberto; Jave‐Suárez, Luis Felipe; Chacón‐Salinas, Rommel; Vallejo-Castillo, Luis; Pérez‐Tapia, Sonia Mayra; Monroy-Garcı́a, Alberto

doi:10.1016/j.cellimm.2017.09.002

Cited by 21 publications

(25 citation statements)

References 45 publications

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“…The results showed that cervical cancer cells express CD73 and CD39 (Figures 2(a) and 2(b)). These data are consistent with the expression of CD73 which plays a significant role in the production of adenosine that suppresses antitumour effector cells, as well as with the fact that cervical cancer cells that are HPV-positive express a higher percentage suggesting that HPV infection contributes to overexpression of CD73 [13]. However, the role of CD39 in cervical cancer is poorly understood.…”

Section: Resultssupporting

confidence: 80%

Cervical Cancer Cells Express Markers Associated with Immunosurveillance

Gutiérrez‐Hoya

Zerecero‐Carreón

Valle‐Mendiola

et al. 2019

Journal of Immunology Research

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Cervical cancer is the second most frequent cancer in women in Mexico, and its development depends on the presence of human papillomaviruses in the uterine cervix. These oncogenic viruses transform cells where the control over cell cycle disappears, and the capacity to induce apoptosis is absent. On the other hand, some mutations confer to the transformed cells the ability to evade recognition by the immune system. The expression of markers of the immune system such as CD95, MICA/B, CD39, CD73, NKp30, NKp46, CD44, CD24, NKG2A, and CTLA-4 was analysed by flow cytometry on cervical cancer cells INBL (HPV 18, stage IVB), HeLa (HPV 18), CaSki (HPV 16), and C33A (HPV-). Our results showed the presence of atypical markers on cervical cancer cells; some of them are molecules involved in tumour cell recognition such as MICA/B and CD95. Other markers associated with immune system escape, such as CD39, CD73, and CTLA-4, were also present. Furthermore, we found that some cervical cancer cells expressed typical markers of NK cells like NKp30, NKp46, NKG2A, and KIR3DL1. It is not clear whether these molecules confer any gain to the tumour cells or if they represent a disadvantage, but we hypothesise that these molecules that are present in cervical cancer cells allow them to mimic in front of the immune system.

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Section: Resultssupporting

confidence: 80%

Cervical Cancer Cells Express Markers Associated with Immunosurveillance

Gutiérrez‐Hoya

Zerecero‐Carreón

Valle‐Mendiola

et al. 2019

Journal of Immunology Research

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“…e adenosine pathway is one of the major inhibitory pathways operating in the TME [28]. Previous studies have indicated that large amounts of adenosine accumulated in the hypoxic TME contribute to suppressing the immune response and promoting tumor progression [29][30][31]. According toÖztürk et al [32], aqueous extracts from S. marianum can inhibit ADA in gastric cancerous tissues and may have an important role in the immune regulation of GC.…”

Section: Discussionmentioning

confidence: 99%

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Shi

Feng

et al. 2019

BioMed Research International

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Background. Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+ T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC. Materials and Methods. Fifty-two GC samples were collected, and the frequency of FoxP3+ Tregs and CD8+ T cells and density ratios of A2aR+/CD8+ T cells, CD39+/FoxP3+ Tregs, and CD73+/FoxP3+ Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3+ Tregs, ratio of A2aR+/CD8+ T cells, and clinicopathological parameters. At the same time, Tregs and CD8+ T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8+ T cells and Tregs with antagonists of A2aR and A2bR in order to examine the alterations in immune function of CD8+ T cells. Results. The density of both FoxP3+ Tregs and A2aR+/CD8+ T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8+ T cells, while this effect could be obviously reduced by applying the antagonist of A2aR or A2aR+A2bR. Moreover, IFN-γ, TNF-α, and perforin generated by CD8+ T cells could also be inhibited through the adenosine A2aR pathway. Conclusions. The FoxP3+ Tregs and A2aR+/CD8+ T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8+ T cells through the A2aR pathway, further leading to immune escape of GC.

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“…Retained HPV gene expression is associated with resistance to CRT and death from cervical cancer HPV, the most common cause of cervical cancer, is known to evade the immune system 27 as well as actively suppress it by decreasing activation and cytotoxic activity of CD8 T-cells 28,29 and by inhibiting stimulator of interferon genes (STING) resulting in decreased type I interferon signaling which others have shown causes a blunted radiation mediated antitumor immune response. 30,31 We therefore hypothesized that the decreased immune response observed in patients DOD is associated with increased HPV gene expression during CRT.…”

Section: Tumors From Patients Dod Have Decreased Lymphocyte Infiltratmentioning

confidence: 99%

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

Cosper

McNair

González

et al. 2019

Intl Journal of Cancer

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More than one-third of patients with locally advanced cervical cancer do not respond to chemoradiation therapy (CRT). We aimed to characterize the transcriptional landscape of paired human cervical tumors before and during CRT in order to gain insight into the evolution of treatment response and to elucidate mechanisms of treatment resistance. We prospectively collected cervical tumor biopsies from 115 patients both before and 3 weeks into CRT. RNA-sequencing, Gene Set Enrichment Analysis and HPV gene expression were performed on 20 paired samples that had adequate neoplastic tissue mid-treatment. Tumors from patients with no evidence of disease (NED) at last follow-up had enrichment in pathways related to the immune response both pretreatment and mid-treatment, while tumors from patients dead of disease (DOD) demonstrated enrichment in biosynthetic and mitotic pathways but not in immune-related pathways. Patients DOD had decreased expression of T-cell and cytolytic genes and increased expression of PD-L2 mid-treatment compared to patients NED. Histological and immunohistochemical analysis revealed a decrease in tumor-associated lymphocytes (TAL) during CRT in all patients but tumors from patients DOD had a significantly more pronounced decrease in TALs and CD8+ cells mid-treatment, which was validated in a larger mid-treatment cohort. Finally, patients DOD retained more HPV E6/E7 gene expression during CRT and this was associated with increased expression of genes driving mitosis, which was corroborated in vitro. Our results suggest that decreased local immune response and retained HPV gene expression may be acting together to promote treatment resistance during CRT in patients with cervical cancer.Additional Supporting Information may be found in the online version of this article.

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Cervical cancer cells suppress effector functions of cytotoxic T cells through the adenosinergic pathway

Cited by 21 publications

References 45 publications

Cervical Cancer Cells Express Markers Associated with Immunosurveillance

Cervical Cancer Cells Express Markers Associated with Immunosurveillance

Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

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Cervical cancer cells suppress effector functions of cytotoxic T cells through the adenosinergic pathway

Cited by 21 publications

References 45 publications

Cervical Cancer Cells Express Markers Associated with Immunosurveillance

Cervical Cancer Cells Express Markers Associated with Immunosurveillance

Adenosine Generated by Regulatory T Cells Induces CD8+T Cell Exhaustion in Gastric Cancer through A2aR Pathway

Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer

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Adenosine Generated by Regulatory T Cells Induces CD8⁺T Cell Exhaustion in Gastric Cancer through A2aR Pathway