Search

JP-7856627-B2 - Methods and compositions for preventing and treating cancer

JP7856627B2JP 7856627 B2JP7856627 B2JP 7856627B2JP-7856627-B2

Inventors

  • タルトゥール，エリク
  • ウダール，ステファーヌ
  • サム，イクアン
  • ベン・ハムーダ，ナディーヌ

Assignees

  • アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル
  • ユニヴェルシテ・パリ・シテ
  • アシスタンス ピュブリク－オピトー ドゥ パリ

Dates

Publication Date
20260511
Application Date
20210727
Priority Date
20200728

Claims (4)

  1. A method for predicting tumor T lymphocyte (LT) dysfunction by determining the interaction between CD27 and CD70, i) A step of determining the level of soluble CD27 (sCD27) in a plasma sample, ii) A step of comparing the level of sCD27 quantified in step i) with its corresponding predetermined reference value, iii) A method comprising the step of concluding that an interaction exists between CD27 and CD70 if the level of sCD27 is higher than its corresponding predetermined reference value, or concluding that no interaction exists between CD27 and CD70 if the level of sCD27 is lower than its corresponding predetermined reference value.
  2. The method according to claim 1, further comprising the step of providing data to conclude that there is tumor lymphocyte (LT) dysfunction if the level of sCD27 is higher than the corresponding predetermined reference value, or providing data to conclude that there is no tumor lymphocyte (LT) dysfunction if the level of sCD27 is lower than the corresponding predetermined reference value.
  3. A method for predicting whether a subject will develop or is susceptible to developing cancer and/or metastatic cancer that expresses CD70, i) A step of determining the level of soluble CD27 (sCD27) in a plasma sample, ii) A step of comparing the level of sCD27 quantified in step i) with its corresponding predetermined reference value, iii) A method comprising the step of providing data to conclude that a subject has or has been diagnosed with a CD70-expressing cancer and/or metastatic cancer if the level of sCD27 is higher than the corresponding predetermined reference value, or providing data to conclude that a subject does not have or does not have a CD70-expressing cancer and/or metastatic cancer if the level of sCD27 is lower than the corresponding predetermined reference value.
  4. A kit or apparatus for predicting tumor T lymphocyte (LT) dysfunction by determining the interaction between CD27 and CD70, comprising means for determining the level of soluble CD27 in a plasma sample.

Description

Field of Invention This invention relates to the field of oncology. In particular, the invention relates to methods and compositions for the prevention and treatment of cancer or metastatic cancer. Background of the Invention Renal cell carcinoma (RCC) accounts for 3-4% of all cancers, with over 300,000 new cases diagnosed worldwide and 140,000 deaths annually (Capitanio et al., 2019). Clear cell renal cell carcinoma (ccRCC) represents 70-75% of the histological subtypes of RCC and is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. This inactivation leads to the stabilization and accumulation of hypoxia-inducible factor-2 (HIF-2). HIF target genes regulate angiogenesis, glycolysis, and apoptosis (Gossage et al., 2015). Therefore, uncontrolled activation of HIF explains why ccRCC tumors are lipid- and glycogen-rich and highly vascular. Localized RCC can be treated with partial or radical nephrectomy. However, approximately 30% of patients with localized ccRCC eventually develop metastasis (Hsieh et al., 2017). Considering the nature of RCC, anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) signaling axis (sunitinib, bevacizumab, axitinib) and mammalian targets of rapamycin (mTOR) inhibitors (everolimus, temsirorumus) are approved for the treatment of metastatic RCC (Hsieh et al., 2017). CD70, a member of the tumor necrosis factor superfamily (TNFSF), is typically present on activated memory B and T lymphocytes, natural killer (NK) cells, and mature dendritic cells (DCs) (Borst et al., 2005; Nolte et al., 2009). CD70 expression is essential for effective immune responses, such as T cell activation and proliferation, memory cell generation, and B cell activation and differentiation (Garcia et al., 2004) (Arens et al., 2004). Interestingly, CD70 is abnormally found in hematological malignancies and solid tumors, particularly ccRCCs (approximately 80%) (Law et al., 2006; Ruf et al., 2015). Furthermore, high expression of CD70 in ccRCCs is associated with reduced survival (Jilaveanu et al., 2012). The consequences of this interaction with immune cells in TMEs remain unclear. CD27, the ligand for CD70, is a costimulatory molecule belonging to the TNF receptor family (Buchan et al., 2018b; Camerini et al., 1991). CD27 is constitutively expressed on naive T cells and central memory T cells, but is downregulated on effector T cells (Mahnke et al., 2013). The CD27-CD70 axis is important for T cell activation during the priming phase. CD27-CD70 interaction induces a series of additional costimulatory signals, leading to the proliferation and differentiation of memory T cells and effector T cells (Nolte et al., 2009). Studies elucidating CD27-CD70 interaction in solid tumors are rare. One study suggested that RCC-expressed CD70 promotes the terminal differentiation of RCC tumor-infiltrating lymphocytes (TILs) (Wang et al., 2012). Two other in vitro studies suggested that CD27-CD70 interaction induces apoptosis in T cells, which functions as an immune evasion mechanism in CD70-expressing glioblastoma and ccRCC (Diegmann et al., 2006; Wischhusen et al., 2002). Finally, soluble CD27 (sCD27) originates from the proteolytic cleavage of transmembrane molecules on activated T cells after CD27-CD70 interaction (Nolte et al., 2009). The role of this soluble receptor and its prognostic value in solid tumors are unknown. Therefore, by identifying the role of soluble CD27 in solid tumors and its interaction with CD70, it becomes possible to understand and discover new tools for treating solid tumors. Summary of the Invention The present invention relates to a method for determining the interaction between CD27 and CD70, comprising the steps of: i) determining the level of soluble CD27 (sCD27) in a biological sample; ii) comparing the level of sCD27 quantified in step i) with a corresponding predetermined reference value; and iii) concluding that an interaction exists between CD27 and CD70 if the level of sCD27 is higher than the corresponding predetermined reference value, or concluding that no interaction exists between CD27 and CD70 if the level of sCD27 is lower than the corresponding predetermined reference value. In particular, the present invention is defined by the claims. Detailed Description of the Invention The inventors have shown that CD70 and CD27 are highly expressed in ccRCC and correlate with metastatic disease. Multiple IFs demonstrate that CD27 + T cells interact with CD70 + tumor cells in the tumor microenvironment (TME). CD27 + T cells are more apoptotic than CD27- T cells in ccRCC. Elevated plasma sCD27 levels were observed in ccRCC patients and correlate with in situ CD27-CD70 interaction. This study demonstrates that CD27-CD70 interaction contributes to the release of sCD27 in peripheral blood in ccRCC. This indicates that sCD27 is a potential biomarker. Apoptosis of CD27 + T cells suggests adverse effects of CD27-CD70 interaction in T cell r