GÉTICA 2021

39 [ F I T C á n c e r - 7 ] Lorenzo Galluzzi Weill Cornell Medical College. New York, USA we performed single-cell RNAseq on CD45 + cells infiltrating MPA/DMBA (M/D)-driven carcinomas established in immunocompetent mice (a unique model of luminal B BC), coupled to bulk RNAseq, bioinformatic analysis on public patient datasets, functional studies on ex vivo immune cells and efficacy studies. Results: We observed that (1) RT and P + ET alone mediate partial efficacy, correlating with accumulation of immunosuppressive T REG and IL17A-producing γδ T cells, respectively, (2) γδ T cell depletion improves the efficacy of P+ET, (3) RT ➝ P + ET mediates superior (but incomplete) tumor control, which is partially offset by CD4 + / CD8 + T cell co-depletion and correlates with lim- ited infiltration by γδ T cells and T REG cells, but accumulation of PD-L1 expressing myeloid cells and M2-polarized TREM2 + macrophages, which have been ascribed robust immunosuppressive effects in multiple settings (Xiong, et al., 2020); and (4) that PD-1 blockage does not amelio- rate the therapeutic effects of RT ➝ P + ET (not shown), pointing to TREM2 + macrophages as to the main culprits for resistance in this setting. Conclusions: Our observations suggest that γδ T cells and TREM2 + macrophages support the resis- tance of HR + BC to CDK4/6i and RT ➝ CDK4/6i, and hence constitute potential targets to delay disease progression. Background/purpose: Hormone receptor + (HR + ) breast cancer (BC) is the most frequent cause of BC-related deaths. CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) emerged as an effective approach for met- astatic HR + BC. However, > 60 % women with HR + BC receiving CDK4/6i+ET ultimately relapse, potentially due to activation of poorly character- ized immunosuppressive pathways in the tumor microenvironment (TME) (Pandey et al. , 2019). Thus, strategies breaking resistance to CDK4/6i + ET in women with HR + BC are urgently awaited. Radiation therapy (RT) mediates immunostim- ulatory effects that only partially overlap with those of CDK4/6i + ET (Rodríguez-Ruiz, et al. , 2020), standing out as a promising therapeutic partner. Consistent with this notion, we recently demonstrated that RT followed by the CDK4/6i palbociclib + ET (RT ➝ P + ET) enables superi- or tumor control in various immunocompetent mouse models of HR + BC (Petroni et al., 2021). These findings have inspired the design of a ran- domized phase II clinical trial testing P+ET vs. RT ➝ P + ET in patients with oligometastatic HR + BC (CIMER, NCT04563507). In this context, we set out to dissect the immunological mechanisms underlying sensitivity vs. resistance to treatment in HR+ BC exposed to P+ET vs. RT ➝ P + ET. Methods: To dissect the impact of these treatments on immune contexture in HR + BC, Radiotherapy as tool to boost immunostimulation by CDK4/6 inhibitors in ER+ breast cancer