Evidence map›Paper›PMID 33416945›Full record

ArticleCancer immunology, immunotherapy : CII2021

Increased expression of adenosine 2A receptors in metastatic renal cell carcinoma is associated with poorer response to anti-vascular endothelial growth factor agents and anti-PD-1/Anti-CTLA4 antibodies and shorter survival.

Takao Kamai, Toshiki Kijima, Toyonori Tsuzuki, Akinori Nukui, Hideyuki Abe, Kyoko Arai, Ken-Ichiro Yoshida

Registry-linked trialOpen access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer immunology, immunotherapy : CII, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04969315 (Phase I/II First-in-Human Study of TT-10), which is not on this map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
3.0field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04969315 phase1 / phase2recruitingnot on this mapstarted 2023, after this paper: background citation

Phase I/II First-in-Human Study of TT-10 (PORT-6), an Adenosine 2A Receptor Antagonist, and PORT-7, an Adenosine 2B Receptor Antagonist, as Single Agents and in Combination in Participants With Advanced Selected Solid Tumors

TypeinterventionalSponsorPortage BiotechRan2023 to 2027Enrolled90ConditionsRenal Cell Cancer, Castrate Resistant Prostate Cancer, Non Small Cell Lung Cancer, Head and Neck Squamous Cell CarcinomaArmsTT-10, TT-4
3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 39 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Review
  5. Insights from Clinical Trials on AACS pharmacology & translational science · 2025
    Review
  6. Review
  7. Review
  8. Review
  9. Article
  10. Review
  11. Review
  12. The Immune Regulatory Role of Adenosine in the Tumor Microenvironment.International journal of molecular sciences · 2023
    Review
  13. Review
  14. Review
  15. Article
  16. Review
  17. Article
  18. Review
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 3 institutions in 1 country.

Takao KamaiDepartment of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan. kamait@dokkyomed.ac.jp.ORCID http://orcid.org/0000-0002-7086-6964
Toshiki KijimaDepartment of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.
Toyonori TsuzukiDepartment of Surgical Pathology, Aichi Medical University, Nagakute, Aichi, Japan.
Akinori NukuiDepartment of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.
Hideyuki AbeDepartment of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.
Kyoko AraiDepartment of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.
Ken-Ichiro YoshidaDepartment of Urology, Dokkyo Medical University, 880 Kitakobayashi Mibu, Tochigi, 321-0293, Japan.
Dokkyo Medical University · JPAichi Medical University · JPDokkyo University · JP

Funding

Japanese Science Progress Society KAKENHI Grants 17K11156, 20K09546
6 · The paper itself

Abstract

backgroundAdenosine and its adenosine 2A receptors (A2AR) mediate the immunosuppressive mechanism by which tumors escape immunosurveillance and impede anti-tumor immunity within the tumor microenvironment. However, we do not know whether the adenosine pathway (CD39/CD73/A2AR) plays a role in renal cell carcinoma (RCC). Therefore, we studied the role of immunosuppression in RCC by assessing the adenosine pathway in patients with RCC treated with anti-vascular endothelial growth factor (anti-VEGF) agents or immune checkpoints inhibitors (ICIs) or both.

methodsIn 60 patients with metastatic RCC, we examined the expression of CD39, CD73, A2AR, and programmed cell death 1 ligand 1 (PD-L1) immunohistochemically in surgically resected tumor tissues and studied the clinicopathological characteristics of these patients. Patients were treated by cytoreductive nephrectomy with systemic therapy with anti-VEGF agent or a combination of the ICIs anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody and programmed cell death 1 (PD-1) antibody.

resultsIncreased expression of A2AR in the primary tumors was associated with metastatic profiles. Patients treated with anti-PD-1 antibody in monotherapy, a combination of anti-PD-1 and anti-CTLA4 antibodies, or anti-VEGF agents showed better response and longer overall survival if the primary tumor had higher PD-L1 expression and lower A2AR expression. In Cox multivariate regression analysis, higher expression of A2AR was associated with shorter overall survival.

conclusionsOur findings suggest that the expression of A2AR and PD-L1 in the primary tumors in RCC might predict the outcomes of treatment with anti-VEGF agents and ICIs and that the A2AR pathway might be a molecular target for immunotherapy.

Indexed as

AdolescentAdultAgedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarcinoma, Renal CellCase-Control StudiesCTLA-4 AntigenFemaleFollow-Up StudiesHumansImmune Checkpoint InhibitorsKidney NeoplasmsMaleMiddle AgedPrognosisADORA2A protein, humanBiomarkers, TumorCTLA-4 AntigenCTLA4 protein, humanImmune Checkpoint InhibitorsPDCD1 protein, humanProgrammed Cell Death 1 ReceptorReceptor, Adenosine A2AVascular Endothelial Growth Factor AVEGFA protein, humanAdenosine 2A receptor (A2AR)CD39CD73PD-L1Renal cell carcinoma

Identifiers

PMID33416945
PMCPMC8195893
OpenAlexW3120424286

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.