Poster Presentation 32nd Lorne Cancer 2020

The role of BH-3 mimetic drugs in overcoming immunotherapy resistance in melanoma (#192)

ZIZHEN MING 1 2 , Bernadette Pedersen 1 2 , Mal Irvine 1 2 , Ashleigh Stewart 1 2 , Su Yin Lim 1 2 , Alexander M. Menzies 2 3 4 , Matteo S. Carlino 2 3 5 , Richard F. Kefford 1 2 5 , Richard A. Scolyer 2 3 6 , Georgina V. Long 2 3 4 , Helen Rizos 1 2
  1. Macquarie University, SYDNEY, NSW, Australia
  2. Melanoma Institute Australia, SYDNEY, New South Wales, Australia
  3. Sydney Medical School, The University of Sydney, SYDNEY, New South Wales, Australia
  4. Royal North Shore and Mater Hospitals, SYDNEY, New South Wales, Australia
  5. Westmead Hospital, SYDNEY, New South Wales, Australia
  6. Royal Prince Alfred Hospital, SYDNEY, New South Wales, Australia

Immune checkpoint inhibitors that block the cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and the programmed cell death protein-1 (PD-1) checkpoint receptors have significantly improved response duration and overall survival of patients with advanced melanoma. Despite these remarkable clinical improvements, many patients will not respond to immune checkpoint inhibition and approximately 25% of responding patients will develop treatment resistance. Established mechanisms of immunotherapy resistance include the loss of antigen presentation, increased expression of immunosuppressive factors, and defects in interferon-gamma (IFN-γ) responses. Alternative combination therapies are now needed to improve response rates and circumvent resistance.

Due to the dysregulated apoptotic pathways in tumourigenesis, the therapeutic potential of BH3-mimetic drugs targeting pro-survival BCL-2 family proteins (BCL-2, BCL-XL, BCL-W and MCL-1) have been reported in different tumour types and are now progressing to the clinic.

In this study, we examined the effects of IFN-γ (a soluble cytokine produced by activated cytotoxic T cells) and BH3-mimetic drugs (S63845, navitoclax), either alone or in combination on a panel of 22 short-term melanoma cell lines established from melanoma patients progressing on anti-PD-1 based therapy (PD-1 PROG cell lines).

The responses of PD-1 PROG cell lines to single-agent IFN-γ was modest; only 6/22 (27%) cell lines responded to IFN-γ treatment by undergoing significant apoptosis (>20%). RNA-sequence analysis revealed increased MCL-1 expression in PD-1 PROG cell lines after exposure to IFN-γ, indicating the potential utility of targeting pro-survival BCL-2 family proteins. Thus, we examined the synergistic effect of S63845/navitoclax and IFN-γ in 8 PD-1 PROG cell lines, including 6 IFN-γ resistant and 2 sensitive cell lines. We found that melanoma cells responded to the combination of IFN-γ and BH-3 mimetic drugs by undergoing significant apoptosis, whereas the monotherapies did not induce potent cell death.  These data suggest that the integration of BH3 mimetics with immune checkpoint inhibitors may prove effective in overcoming immunotherapy resistance in melanoma. Further work on response mechanisms is currently under investigation in our group.