Abstract
BackgroundPatients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite aggressive multimodal therapy. ATC has a high prevalence of BRAFV600E mutations and is associated with an immunosuppressive microenvironment; we previously demonstrated that the combination of BRAF inhibitor and checkpoint inhibitor immunotherapy synergistically reduce tumour volume in an immunocompetent mouse model of orthotopic ATC.MethodsWe again utilised our mouse model of ATC to assess the combination of BRAFV600E inhibitor PLX4720 and anti-PD-L1 or anti-PD-1 antibody on survival, and performed immune cell profiling of lymphoid and myeloid-lineage cells during maximal treatment response and tumour regrowth.ResultsCombination therapy dramatically improved mouse survival. Maximal tumour reduction was associated with increases in the number and cytotoxicity of CD8+ T cells and NK cells, as well as increases in mostly M1-polarised tumour-associated macrophages (TAM) and decreases in myeloid-derived suppressor-like cells. Regrowth of tumour occurred after 2–3 weeks of ongoing combination therapy, and was most significantly associated with decreased TAMs and a dramatic increase in M2-polarisation.ConclusionsCombination of PLX4720 and anti-PD-L1/PD-1 antibody dramatically reduced tumour volume, prolonged survival and improved the anti-tumour immune profile in murine ATC. Tumour growth inevitably recurred and demonstrated re-emergence of an immunosuppressive tumour microenvironment.
Highlights
Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite aggressive multimodal therapy
Treatment with PLX4720 led to significant tumour volume reduction (259 ± 65 mm3, 41% tumour growth inhibition, p < 0.01), whereas dramatic tumour reduction was seen with PLX4720 + anti-PD-1 (160 ± 47 mm3, 61% tumour growth inhibition, p < 0.01) and PLX4720 + anti-PD-L1 (170 ± 67 mm3, 64% tumour growth inhibition, p < 0.01), consistent with our prior work (Fig. 1b)
A recent GWAS showed that BRAFV600E-mutant thyroid cancers tend to have higher levels of T cells, M2polarised tumour-associated macrophages (TAM), and lower levels of NK cells.[25,36]
Summary
Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite aggressive multimodal therapy. ATC has a high prevalence of BRAFV600E mutations and is associated with an immunosuppressive microenvironment; we previously demonstrated that the combination of BRAF inhibitor and checkpoint inhibitor immunotherapy synergistically reduce tumour volume in an immunocompetent mouse model of orthotopic ATC. METHODS: We again utilised our mouse model of ATC to assess the combination of BRAFV600E inhibitor PLX4720 and anti-PD-L1 or anti-PD-1 antibody on survival, and performed immune cell profiling of lymphoid and myeloid-lineage cells during maximal treatment response and tumour regrowth. Regrowth of tumour occurred after 2–3 weeks of ongoing combination therapy, and was most significantly associated with decreased TAMs and a dramatic increase in M2polarisation. CONCLUSIONS: Combination of PLX4720 and anti-PD-L1/PD-1 antibody dramatically reduced tumour volume, prolonged survival and improved the anti-tumour immune profile in murine ATC. Despite initial impressive response rates, the durability of response is limited owing to development of resistance.[9,10,11] Since reactivation of downstream MEK is a frequent mechanism of resistance, MEK inhibition (MEKi) is a useful adjunct; the combination of BRAFi (dabrafenib) and MEKi (trametinib) demonstrated an overall response rate of 69% in a recent phase II clinical trial which has led to FDA approval of the combination.[12]
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