Abstract 1145: Comparative spatial transcriptomic analysis of tumor microenvironment responses to conventional chemotherapy and immunotherapy in triple-negative breast cancer
Authors: Do-Eon Gu, Jiyeon Hyeon, Eun Seop Seo, Hae Hyun Jung, Jonghan Yu, Seok Won Kim, Young-Hyuck Im, Ji-Yeon Kim, Woong-Yang Park
Journal: Cancer Research (2024)

Abstract Background: In triple negative breast cancer (TNBC), pembrolizumab in combination with cytotoxic chemotherapy has proven its efficacy and improved survival outcome. Previous studies demonstrated that PD-L1 expression, tumor mutational burden as well as certain neo-antigens were associated with response to pembrolizumab but there were no biomarkers predicting the response of pembrolizumab of TNBC in neoadjuvant setting. Therefore, tumor microenvironment (TME) evaluation would be warranted to understand the mechanism of action of pembrolizumab in TNBC. Methods: We employed the Xenium In Situ platform, a cutting-edge spatial transcriptomics tool, capable of mapping hundreds of transcripts within individual cells. Using a 380-plex gene panel, we analyzed formalin-fixed, paraffin-embedded TNBC sections treated with weekly paclitaxel with carboplatin followed by doxorubicin with cyclophosphamide (CTx) with/without pembrolizumab in neoadjuvant setting. We analyzed detailed cellular compositions of tumors, encompassing immune and stromal cells, across over one million cells and we attempted to identify various cell types and states, previously characterized through single-cell RNA sequencing, and assess their spatial heterogeneity within the TME with regard to treatment strategy and the response to treatment. Results: We collected 19 serial samples from 13 patients including 12 pre-treatment and seven post-treatment samples. Among seven post-treatment samples, one was collected after three weeks of the first treatment and one was after disease relapse. Of 13 patients, seven patients had received pembrolizumab with cytotoxic chemotherapy and four out of seven have achieved pathologic complete response (pCR). In six patients treated with only cytotoxic chemotherapy, only two achieved pCR. Our analysis revealed significant alterations in the spatial organization of cells in both the pembrolizumab with CTx and CTx-only groups. Notably, an increase in CD8 T cells and plasma cells following treatments was pronounced in post-treatment samples from patients in the pembrolizumab with CTx group. We also observed treatment-specific variations in ligand-receptor interactions between immune cells and cancer cells. Conclusion: This study provides an in-depth analysis of the TME in TNBCs in response to pembrolizumab with CTx. Utilizing the Xenium In Situ platform, we uncovered significant disparities in the immune cell population according to the application of pembrolizumab. Our findings underscore the complexity of TME responses and highlight the potential of spatial transcriptomics in informing tailored treatment strategies for TNBC. Citation Format: Do-Eon Gu, Jiyeon Hyeon, Eun Seop Seo, Hae Hyun Jung, Jonghan Yu, Seok Won Kim, Young-Hyuck Im, Ji-Yeon Kim, Woong-Yang Park. Comparative spatial transcriptomic analysis of tumor microenvironment responses to conventional chemotherapy and immunotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1145.