Atsunari Kawashima1,2, Takayuki Kanazawa3,4, Kumiko Goto5,6, Mitsunobu Matsumoto5,6, Akiko Morimoto-Okazawa5, Kota Iwahori5, Takeshi Ujike7, Akira Nagahara7, Kazutoshi Fujita7, Motohide Uemura7, Norio Nonomura7, Hisashi Wada5. 1. Department of Urology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. kawashima@uro.med.osaka-u.ac.jp. 2. Department of Clinical Research in Tumour Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. kawashima@uro.med.osaka-u.ac.jp. 3. Department of Clinical Research in Tumour Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. takayuki.kanazawa@shionogi.co.jp. 4. Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan. takayuki.kanazawa@shionogi.co.jp. 5. Department of Clinical Research in Tumour Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. 6. Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan. 7. Department of Urology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Abstract
OBJECTIVES: To clarify comprehensive immunological signature patterns of tumour tissue-infiltrating lymphocytes in patients with renal cell carcinoma and show its clinical significance. MATERIALS AND METHODS: We investigated the surface marker expressions of tumour tissue-infiltrating lymphocytes quantitatively and classified them based on their functional populations. We extracted 109 sets of tumour tissue-infiltrating lymphocytes from 80 patients who underwent surgical resection of renal cell carcinoma, of which 44 tumour tissue-infiltrating lymphocytes were multiply extracted from 15 patients. Each tumour tissue-infiltrating lymphocyte was characterised on the basis of functional T-cell populations using ten surface marker expressions measured by flow cytometry. RESULTS: All sets of the tumour tissue-infiltrating lymphocytes were classified into three groups, which correlated significantly with Fuhrman grade (OR 0.253, 95% CI 0.094-0.678, P = 0.006). Importantly, both overall metastasis-free survival (HR 0.449, 95% CI 0.243-0.832, P = 0.011) and recurrence-free survival (HR 0.475, 95% CI 0.238-0.948, P = 0.035) of the patients with the higher marker expressions were significantly inferior to those of the patients with the lower marker expressions by multivariate analysis. Six specific genes for this classification identified by microarray analysis verified our results using the TCGA KIRC data set. In addition, we discovered the presence of intra-tumoural diversity in the classification of 3 (20%) of the 15 patients. CONCLUSIONS: This study showed that the presence of classable diversity in the immunological signature of tumour tissue-infiltrating lymphocytes correlated with prognosis and tumour aggressiveness that was observed even within individual tumours in some patients with renal cell carcinoma.
OBJECTIVES: To clarify comprehensive immunological signature patterns of tumour tissue-infiltrating lymphocytes in patients with renal cell carcinoma and show its clinical significance. MATERIALS AND METHODS: We investigated the surface marker expressions of tumour tissue-infiltrating lymphocytes quantitatively and classified them based on their functional populations. We extracted 109 sets of tumour tissue-infiltrating lymphocytes from 80 patients who underwent surgical resection of renal cell carcinoma, of which 44 tumour tissue-infiltrating lymphocytes were multiply extracted from 15 patients. Each tumour tissue-infiltrating lymphocyte was characterised on the basis of functional T-cell populations using ten surface marker expressions measured by flow cytometry. RESULTS: All sets of the tumour tissue-infiltrating lymphocytes were classified into three groups, which correlated significantly with Fuhrman grade (OR 0.253, 95% CI 0.094-0.678, P = 0.006). Importantly, both overall metastasis-free survival (HR 0.449, 95% CI 0.243-0.832, P = 0.011) and recurrence-free survival (HR 0.475, 95% CI 0.238-0.948, P = 0.035) of the patients with the higher marker expressions were significantly inferior to those of the patients with the lower marker expressions by multivariate analysis. Six specific genes for this classification identified by microarray analysis verified our results using the TCGA KIRC data set. In addition, we discovered the presence of intra-tumoural diversity in the classification of 3 (20%) of the 15 patients. CONCLUSIONS: This study showed that the presence of classable diversity in the immunological signature of tumour tissue-infiltrating lymphocytes correlated with prognosis and tumour aggressiveness that was observed even within individual tumours in some patients with renal cell carcinoma.
Entities:
Keywords:
Heterogeneity; Hot cluster; Immunological classification; Intra-tumour diversity; PD-1; Tim-3
Authors: Saskia D van Asten; Rosa de Groot; Marleen M van Loenen; Suzanne M Castenmiller; Jeroen de Jong; Kim Monkhorst; John B A G Haanen; Derk Amsen; Axel Bex; Robbert M Spaapen; Monika C Wolkers Journal: Oncoimmunology Date: 2021-01-21 Impact factor: 8.110