Patients with anaplastic thyroid cancer (ATC) have a median survival of 6 months. Chemotherapy in combination with surgery and radiation may modestly extend survival of ATC confined to the neck but offers minimal benefit in patients with metastatic disease. Recently, combination treatment using the RAF inhibitor dabrafenib with the MEK inhibitor trametinib showed a 69% ORR and dramatic tumor regression in BRAFV600E- driven ATCs, which is the first meaningful advance in the treatment of this disease. In contrast, response to this same combination in BRAF-driven differentiated thyroid cancer (DTC) is 33%. The remarkable dab/tram effects in BRAF-ATCs provide a roadmap to explore the therapeutic vulnerabilities in this disease. A hallmark of ATCs is their heavy infiltration with tumor-associated macrophages (TAMs) with M2 polarization. TAMs are associated with a worse prognosis in thyroid and other cancers, attributed in part to their suppression of immune surveillance. Although ATCs are also enriched for T cells, a pilot trial of immune checkpoint blockade (ICB) showed no efficacy in this disease, including in two ATCs with microsatellite-instability, predicted to harbor numerous neoantigens. Based on a mouse model of Braf-driven ATC that we developed, which recapitulates the immune milieu of the human disease, we propose that profound MAPK pathway inhibition blocks production of tumor-derived cytokines governing TAM recruitment and maintenance, leading to their depletion and the consequent de-repression of T cell cytotoxicity. We hypothesize that MAPK blockade primarily accounts for this TME response, and that TAMs and MAPK regulation of ATC antigen presentation play a central role in the process. To understand the relative contribution of these mechanisms we will: 1) Identify ATC cell-derived cytokines that recruit infiltrating myeloid cell populations. We identified a MAPK- driven cytokine panel in BRAF-ATCs and will determine individual cytokine contributions to myeloid recruitment using genetic and pharmacological approaches. 2) Determine the role of TAMs in response to therapy. We will first investigate whether TAMs block T-cell responses to model antigens (Pmel and/or Tyrp1) in ATCs in vivo. We will perform genetic or pharmacological depletion of TAMs to determine the optimal approach to enhance T cell responses, then determine the effects of TAM depletion or repolarization on T cell response to tumor cell autonomous neoantigens, and whether these can further enhance efficacy of ICB in mouse Braf/p53 ATCs. 3) Determine the role of tumor cell antigen presentation in T cell response following MAPK inhibition and whether the magnitude or duration of response can be enhanced by Pd1 blockade. 4) Determine sequential changes in the immune landscape of human BRAFV600E ATCs in response to preoperative treatment with dab/tram and during a combination trial of dab/tram with the PD1 inhibitor Cemiplimab.
BRAF-mutant anaplastic thyroid cancers are almost always incurable and frequently lethal. They are heavily infiltrated by myeloid and T cells. We propose to investigate the relative contribution of myeloid cell depletion and antigen presentation by tumor cells in their remarkable response to MAPK inhibition, because they point to ATC vulnerabilities that could be targeted through alternative approaches, as well as to eventual mechanisms of resistance to this therapy.
