Tumor infiltrating lymphocytes (TILs) inside a tumor is associated with cell proliferation and better survival but not with chemotherapy response in breast cancer
Rongrong Wu1, Masanori Oshi1, Mariko Asaoka2, Takashi Ishikawa2, Kazuaki Takabe*1
1Surgical Oncology, Roswell Park Comprehensive Cancer Center, Clarence, NY; 2Breast Oncology, Tokyo Medical University, Tokyo, Tokyo, Japan
Objective: To assess the clinical relevance of tumor-infiltrating lymphocytes (TILs) inside the bulk tumor of breast cancer (BC) patients.
Background: Abundance of TILs that is known to correlate with response to chemotherapy and survival of BC, is assessed pathologically at the peripheral region of a tumor. Although it is standardized with international guideline, pathological evaluation of TILs cannot avoid operator bias, whereas computational deconvolution of the transcriptome of a tumor provides objective data. Given that TILs directly effect on cancer cells, we hypothesized that TILs inside a bulk tumor have stronger correlation with the clinical features of BC, namely response to neoadjuvant chemotherapy (NAC). We developed a novel score to estimate the amount of intratumoral TILs in patients’ BC to test this hypothesis.
Methods: A total of 5870 primary breast cancers which have bulk tumor RNA-sequence data associated with clinical features (TCGA, SCAN-B, GSE163882, GSE25066, and GSE194040 cohorts) were analyzed and validated. Based upon the sampling criteria of all the cohorts, gene expression signals from inside the bulk tumors were analyzed.
Results: Among several deconvolution algorithms, entire sum of all the types of lymphocytes estimated by xCell algorithm was chosen as the TIL score because of the highest correlation with multiple signals that represent TILs. The cohorts were divided to high or low TIL tumors by median cut-off and amounts 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. To this end, immune-related features were similar between the TILs inside a tumor assessed using TIL score and pathology-assessed TILs at the peripheral region of a tumor. Interestingly, high TILs were significantly associated with higher mutation rates only in ER+HER2- subtype, which was the subtype that most strongly correlated with cell proliferation biologically, pathologically, and molecular biologically. Surprisingly, intratumoral TILs showed low area under the curve (AUC) for predicting pathological Complete Response after NAC (AUC < 0.6). Gene expression-based scores generated by LASSO model showed low AUC in all the cohorts as well (AUC < 0.65).
Conclusion: TILs inside the tumor estimated by transcriptomic signature is associated with cell proliferation in ER+HER2- and better survival in HER2+ and triple negative breast cancer; however, it was not as consistently associated with complete response after neoadjuvant chemotherapy as pathologically-assessed TILs.
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