Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

Determining if Osteopontin is an immune checkpoint of KRAS mutant Colorectal Cancer (#170)

Bianca A Nowlan 1 , Jennifer Borowsky 1 2 3 , Chang Su 1 , Lochlan Fennel 1 , Troy Dumenil 1 , Diane McKeone 1 , Simon Tria 1 , Catherine Bond 1 , Gunter Hartel 1 , Jonathan Nowak 4 , Matthew Burge 5 , John Liu 1 6 , Andressa Dias Costa 7 , Shuji Ogino 8 , Neal Walker 6 , Ian Brown 6 , Mark Bettington 6 , Barbara Leggett 1 9 , Vicki Whitehall 1 10
  1. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  2. School of Medicine, The University of Queensland, Brisbane, QLD, Australia
  3. Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
  4. Brigham and Women's Hospital, Boston, , MA, United States
  5. The Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
  6. Envoi Pathology, Kelvin Grove, QLD, Australia
  7. Dana-Farber Cancer Institute, Boston, MA, United States
  8. Department of Pathology, Brigham and Women's Hospital Harvard Medical School, Boston, MA, United States
  9. Royal Brisbane and Womens Hospital Gastroenterology, Herston, QLD, Australia
  10. Conjoint Internal Medicine Laboratory, Pathology Queensland, Brisbane, QLD, Australia

Colorectal cancer (CRC) is the 2nd most common cause of cancer mortality with 15,500 newly diagnosed cases in Australia each year. Early-stage tumours have a 91% 5-year survival rate, but this drops dramatically to 16% in the metastatic setting, of which the majority metastasize to the liver. This dismal 5-year survival rate for late stage disease is mainly due to the lack of effective therapies for metastatic CRC (mCRC). Revolutionary therapies using immune checkpoint blockade have been ineffective for the vast majority of patients with mCRC. We identified a particularly aggressive, treatment refractory subgroup of CRC characterised by KRAS mutation and upregulation of genes associated with epithelial mesenchymal transition (EMT), angiogenesis and TGFb signalling. We also observed significant upregulation of the SPP1 transcript in these cancers. SPP1 encodes the Osteopontin (OPN) protein, which is associated with poor prognosis due to the effect OPN has on immune suppression, increasing treatment resistance. We hypothesise that OPN inhibition will reverse the immunosuppressive tumour microenvironment and enhance sensitivity to immunotherapy. To test our hypothesis, we developed a mouse model that recapitulates this human tumour subgroup through increased EMT, angiogenesis, TGFb signalling and increased SPP1 expression determined by RNAseq analysis. Cancer organoids were implanted subcutaneously or via portal vein injection into mice to determine treatment effectiveness in primary cancers or liver metastases. Tumours were allowed to develop in size and then grouped into treatment groups with either control, anti-PD-1, anti-OPN, TGFβ-R1 small molecule inhibition, or a combination of these therapies. Preliminary results suggest the combination of PD-1, OPN and TGFβ-R1 inhibition effectively reduces primary tumour growth.