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20 Development of VISTA-centric tumor immunophenotyping as a novel approach for identification of potential biomarkers for anti-VISTA therapy
  1. Andrey Ugolkov1,
  2. Rosanna Hok1,
  3. Reinhard von Roemeling1,
  4. Alexander Martin2 and
  5. Robert Martell1
  1. 1Curis, Lexington, MA, USA
  2. 2Tufts Medical Center, Boston, MA, USA


Background V-domain immunoglobulin suppressor of T cell activation (VISTA) is a negative checkpoint regulator of immune cells. VISTA has been recognized as a potential mediator of resistance to anti-PD-1 and anti-CTLA-4 immunotherapies in cancer patients. Targeting the VISTA signaling pathway has been suggested as a promising approach for overcoming resistance to current immune checkpoint therapies. Herein, we report the design, development, and analytical algorithm for comprehensive VISTA-centric tumor immunophenotyping to explore potential tumor biomarkers for novel anti-VISTA therapeutic antibody CI-8993, currently under clinical development in Phase 1 trial.

Methods Formalin-fixed paraffin embedded (FFPE) tumor tissue sections from 10 cases of non-small cell lung carcinoma (NSCLC) were purchased from NovoVita Histopath Laboratory. Serial tumor tissue sections were double-immunostained with VISTA combined with CD8 (cytotoxic T cell marker), CD4 (T helper cell marker), CD11b (myeloid cell marker), CD68 (monocyte/macrophage marker), CD56 (NK cell marker), CD19 (B cell marker) or Programmed Death-Ligand 1 (PD-L1).

Results Immunohistochemical analysis revealed the presence of CD8+ cells (9/10 cases), CD4+ cells (3/10 cases), CD11b+ cells (10/10 cases), CD68+ cells (10/10 cases), CD56+ cells (4/10 cases) and CD19+ cells (8/10 cases) in lung tumors. Using double IHC staining, we found that VISTA was expressed in CD8+ cells (5/9 tumors), CD11b+ cells (5/10 tumors) and CD19+ cells (5/8 tumors), whereas VISTA was hardly detectable in CD4+, CD68+ or CD56+ cells. Expression of PD-L1 was detected in cancer cells in 6/10 tumors, whereas VISTA-pos cancer cells were revealed in 1/10 tumors. We developed an algorithm for evaluation of VISTA-centric tumor immunophenotyping and demonstrated that every tumor has a unique cell-type-specific pattern of VISTA expression which could serve as a potential biomarker.

Conclusions Our results demonstrate that comprehensive VISTA-centric immunophenotyping enables spatially resolved and cell-type-specific characterization of VISTA expression in solid tumors and can serve as applicable bioanalytical approach for identification of potential biomarkers to guide anti-VISTA therapeutic treatment decisions.

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