Abstract 2032: Intratumoral tumor infiltrating lymphocytes is associated with cell proliferation and better survival but not with response to chemotherapy
Authors: Wu Rongrong , Oshi Masanori , Asaoka Mariko , Nagahashi Masayuki , Yan Li , Miyoshi Yasuo , Ishikawa Takashi , Takabe Kazuaki 
Published: June 2023

Abstract
Introduction: Abundance of tumor infiltrated lymphocytes (TILs) in the peripheral region of tumor assessed pathologically is associated with improved response to chemotherapy and better prognosis in Her2+ and triple-negative breast cancer (TNBC). Since recent progress in bioinformatics has allowed for computational deconvolution of bulk tumor, we investigated the clinical relevance of intratumoral TILs in primary breast cancer and response to neoadjuvant chemotherapy (NAC).
Methods: A total of 4139 bulk tumor RNA sequencing data were analyzed for the association of high intratumoral TILs with clinicopathologic factors and biology in primary breast cancer cohorts of TCGA and SCAN-B. Total of 1719 bulk samples from three other cohorts (GSE163882, GSE25066, and GSE194040) were utilized to investigate the association between pathologic complete response rate (pCR) to neoadjuvant chemotherapy and intratumoral TILs.
Results: Among several deconvolution algorithms, the sum of xCell lymphocytes was chosen to estimate intratumoral TIL since it correlated the strongest with multiple signals that represent lymphocytes. The cohorts were divided into high or low TIL tumor by median cut-off, and number of TILs in high-TIL ER+/Her2- was roughly the same as that of low-TIL TNBC. As expected, high TILs were associated with better disease specific survival in Her2+ and TNBC subtypes consistently in TCGA and SCAN-B cohorts. Immune-related gene sets were uniformly enriched to high TIL tumors regardless of subtype, and the difference in cytolytic activity by TILs were the largest in TNBC. Macrophages, dendritic cells, lymphatic and blood endothelial cells were infiltrated in TIL high tumors. Thus, estimated intra-tumor TILS showed similar immune-related characteristics with pathology-assessed TILs. However, ER+/Her2- was most strongly correlated with cell proliferation biologically, pathologically, and molecular biologically. High TIL was significantly associated with higher mutation related scores only in ER+HER2-. Unexpectedly, intratumoral TILs and all the types of lymphocytes showed low AUC for predicting pCR to NAC (AUC &lt; 0.6). Gene expression-based scores generated by LASSO model showed low AUC in all the cohorts neither (AUC &lt; 0.65).
Conclusion: Transcriptomic signature of Intratumoral TILs is associated with cell proliferation in ER+HER2- breast cancer and better survival in HER2+ breast cancer and TNBC but is not as consistently associated with response to neoadjuvant chemotherapy as pathologically assessed TILs.
Citation Format: Rongrong Wu, Masanori Oshi, Mariko Asaoka, Masayuki Nagahashi, Li Yan, Yasuo Miyoshi, Takashi Ishikawa, Kazuaki Takabe. Intratumoral tumor infiltrating lymphocytes is associated with cell proliferation and better survival but not with response to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2032.