Poster Presentation 30th Lorne Cancer Conference 2018

A role for NK cells in melanoma response to targeted therapies (#216)

Claire Martin 1 , Carleen Cullinane 1 2 , Nicole Haynes 1 , Grant McArthur 1 2 3 , Karen Sheppard 1 2 4
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
  3. Department of Pathology, University of Melbourne, Parkville, VIC, Australia
  4. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia

Melanoma patients show high response rates to therapies targeting the MAPK pathway, such as mutant BRAF-inhibitors, however these responses frequently lack durability and resistance to these inhibitors limits their efficacy. We have previously shown that a combination of BRAF-inhibitor PLX4720 and CDK4/6-inhibitor Palbociclib is highly effective at controlling melanoma growth and preventing development of resistance. Immunotherapies also provide clear clinical benefit to melanoma patients, and there is growing evidence that targeted therapies can impact the immune system. Here we investigate the role of the innate immune system, specifically NK cells, in the response to BRAF inhibitors. NK cell activity is required for the ability of BRAF-inhibitors to prevent lung metastases in syngeneic models of melanoma, however a role for NK cells in controlling primary tumours has not been clearly shown. In xenograft models, we show PLX4720 treatment strongly inhibits melanoma growth in Nude mice, however this effect is mitigated in NSG mice. These data indicate that components of the immune system present in Nude but not NSG animals may contribute to the inhibition of tumour growth. Addition of Palbociclib to PLX4720 caused tumour regression in both Nude and NSG mice, supporting the strong efficacy of this combination therapy identified in vitro. PLX4720 alone tended to increase NK cell infiltration into tumours and the combination of both PLX4720 and Palbociclib therapy significantly increased NK cell infiltration. NK cell migration and recruitment is mediated by chemokines. PLX4720 treatment increases expression of CCL2 and CCL5 in melanoma cell lines, and this effect is enhanced by the addition of Palbociclib. This increased chemokine expression could contribute to the increased infiltration of NK cells into tumours. We show that in vitro NK cells have cytotoxic activity against melanoma and this activity is not impaired by BRAF or CDK4 inhibitors. NK cells may therefore contribute to control of tumours in response to these targeted therapies, and are a potential target for immunotherapy in melanoma.