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Prognostic role of the innate immune signature CD163 and “eat me” signal calreticulin in clear cell renal cell carcinoma

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Abstract

The effects of the innate immune status on patients with clear cell renal cell carcinoma (ccRCC) currently remain unknown. We herein provided more extensive information about the inner landscape of immunobiology of ccRCC. In total, 260 ccRCC samples from three different cohorts consisting of 213 primary tumors and 47 metastases were obtained. We focused on five representative innate immune signatures, CD68, CD163, the “eat me” signal calreticulin, the “don't eat me” signal CD47, and signal regulatory protein α, and examined the role of each signature by quantitative immunohistochemistry. We then conducted an integrated genome mutation analysis by next-generation sequencing. Among the five markers, high CD163 and low calreticulin expression levels were prognostic in ccRCC. The application of a new risk model based on CD163 and calreticulin levels, named the innate immune risk group (high risk: high-CD163/low calreticulin, intermediate risk: high-CD163/high calreticulin or low CD163/low calreticulin, low risk: low-CD163/high calreticulin), enabled the sequential stratification of patient prognosis and malignancy. Although organ-specific differences were observed, metastases appeared to have a higher innate immune risk, particularly in the lungs, with 50% of ccRCC metastases being classified into the high-risk group according to our risk score. An analysis of genomic alterations based on the innate immune risk group revealed that alterations in the TP53/Cell cycle pathway were highly prevalent in high-risk ccRCC patients according to two innate immune signatures CD163 and calreticulin. The present results provide insights into the immune-genomic biology of ccRCC tumors for innate immunity and will contribute to future therapies focused on the innate immune system in solid cancers.

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Acknowledgements

The present study was supported by Grants-in-Aid for Scientific Research (KAKENHI 21K09411 to T.A.; 19H03792, 21K19414, and 22H03217 to N.T), the Takeda Science Foundation (N.T.), the Kobayashi Foundation for Cancer Research (N.T.), the SGH Foundation for Cancer Research (to N.T.), the Princess Takamatsu Cancer Research Fund (to N.T.), and the Keio Gijuku Academic Development Funds (to N.T.).

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Authors and Affiliations

  1. Department of Urology, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Tadatsugu Anno, Nobuyuki Tanaka, Kimiharu Takamatsu, Kyohei Hakozaki, Ryohei Kufukihara, Yuto Baba, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno & Mototsugu Oya

  2. Department of Diagnostic Pathology, Keio University Hospital, Tokyo, 160-8582, Japan

    Shuji Mikami

  3. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan

    Hiroshi Nishihara

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  1. Tadatsugu Anno
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  2. Nobuyuki Tanaka
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Contributions

T.A. and N.T. designed the study. T.A., K.T., K.H., R.K., Y.B., and S.M. performed the experiments. T.T., K.M., S.M., T.K., and R.M. provided conceptual advice. H.N. performed genetic experiments. T.A. and N.T. wrote the manuscript with inputs from M.O.

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Correspondence to Nobuyuki Tanaka.

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Anno, T., Tanaka, N., Takamatsu, K. et al. Prognostic role of the innate immune signature CD163 and “eat me” signal calreticulin in clear cell renal cell carcinoma. Cancer Immunol Immunother 72, 1779–1788 (2023). https://doi.org/10.1007/s00262-023-03369-8

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