Flash Talk & E-Poster - Virtual Presentation 33rd Lorne Cancer Conference 2021

Understanding cancer immune evasion at the clonal level using DNA barcoding (#21)

Louise Baldwin 1 2 , Nenad Bartonicek 1 2 , Jessica Yang 1 , Niantao Deng 1 2 , Daniel L Roden 1 2 , Sunny Z Wu 1 2 , Chia-Ling Chan 1 , Ghamdan Al-Eryani 1 2 , Alexander Swarbrick 1 2 , Simon Junankar 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia

Cancer cells must find mechanisms to evade the immune system if they are to grow sufficiently to cause disease. Evidence suggests that this occurs through a process called cancer immuno-editing, whereby the most immunogenic sub-populations of cells are eliminated by the immune system. Understanding this process in greater detail will enable improvements to immunotherapy regimens and lead to better patient outcomes. This is particularly important for the cancer types such as breast cancer that have shown only limited response to the current immunotherapies. Using cellular DNA barcoding we track the clonal response of cancer cells to the immune system during primary tumour growth of the EMT6 syngeneic mouse model of breast cancer and in response to immunotherapy with anti-PD1 and anti-CTLA4. We find that the anti-cancer immune response markedly restricts the number of clones that grow at the primary tumour site, which is further restricted by treatment with immunotherapy. Using the more metastatic 4T1 model revealed another round of immunoediting during metastatic dissemination. We determine that both CD8 T-cells and NK cells contribute to this immunoediting. Furthermore, we identified two rare pre-existing immunotherapy resistant clones that expand during growth in immuno-competent mice and which have overlapping transcriptional signatures of resistance. We show that a gene signature derived from the overlapping genes is predictive of survival in the METABRIC basal-like breast cancer patient cohort. However, we also found that each clone had unique expression of canonical immune evasion pathways, with one clone significantly downregulating MHC expression and the other upregulating PD-L1 expression. These findings suggest that immunoediting leads to the selection of pre-existing breast cancer cell populations that can drive immunotherapy resistance by multiple mechanisms. These findings will assist in the discovery of novel immunotherapies that avoid or overcome these resistance pathways and lead to the improved response of breast cancer patients to immunotherapy.