Efficacy of neoadjuvant immunotherapy is mediated through the selective expansion of tumour-specific CD8<sup>+</sup> T cells with a memory precursor phenotype — ASN Events
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  3. Efficacy of neoadjuvant immunotherapy is mediated through the selective expansion of tumour-specific CD8+ T cells with a memory precursor phenotype

Efficacy of neoadjuvant immunotherapy is mediated through the selective expansion of tumour-specific CD8+ T cells with a memory precursor phenotype (#30)

Jake S O'Donell 1 2 , Jing Liu 2 , Stacey Allen 2 , Scott N Mueller 3 , Mark J Smyth 1 , Michele W Teng 2
  1. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
  2. Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  3. Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity; The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Melbourne, Victoria, Australia

Immunotherapy stands ready to become a pillar of cancer treatment with the approval of multiple agents for the treatment of cancer. Although immunotherapy has demonstrated efficacy in advanced cancers, its scheduling and efficacy with surgery to treat earlier stages of cancer and prevent distant metastases have not been systematically examined. We previously demonstrated in two orthotopic mouse models of spontaneously metastatic breast cancer (4T1.2, E0771), the significantly greater therapeutic power of neoadjuvant compared with adjuvant immunotherapies in the context of cancer surgery. Elevated and sustained peripheral tumor-specific gp70-CD8+ T cells after neoadjuvant immunotherapy underpinned the outcome. Furthermore, neoadjuvant immunotherapy generated long-lived effector memory (TEM) and central memory (TCM) gp70-CD8+ T cells, detectable in the blood of cured mice 150 days after tumour challenge. We hypothesised that the improved efficacy of neoadjuvant over adjuvant immunotherapy to eradicate metastases is mediated through the generation of better quality and quantity of tumour-specific gp70-CD8+ T cells. In this study, we demonstrated that neoadjuvant compared to adjuvant anti-PD1+anti-CD137 immunotherapy treatment significantly expanded gp70-CD8+ T cells in the spleen, blood and lungs of 4T1.2 tumour-bearing mice. Within the expanding gp70-CD8+ T cells, we observed an increased proportion of these T cells displaying a memory precursor phenotype (MPEC) as defined by low expression of KLRG1 and high expression of CD127. This expansion was dependent on the presence of the primary tumour and its appropriate resection soon after neoadjuvant immunotherapy as it prevented these proliferating tumour-specific CD8+ T cells from developing an exhausted phenotype as characterized by changes in PD-1 expression. Overall, these preliminary findings offer insight into the pathways that are activated by neoadjuvant immunotherapy, which may allow for their selective targeting to further improve the efficacy of immunotherapies.

 

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