Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer
Koji Inamori, … , Masaaki Ito, Hiroyoshi Nishikawa
Koji Inamori, … , Masaaki Ito, Hiroyoshi Nishikawa
Published March 23, 2021
Citation Information: JCI Insight. 2021;6(9):e137365. https://doi.org/10.1172/jci.insight.137365.
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Research Article Oncology

Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer

Abstract

Patients with colorectal cancers (CRCs) generally exhibit improved survival through intensive lymph node (LN) dissection. However, recent progress in cancer immunotherapy revisits the potential importance of regional LNs, where T cells are primed to attack tumor cells. To elucidate the role of regional LN, we investigated the immunological status of nonmetastatic regional LN lymphocytes (LNLs) in comparison with those of the tumor microenvironment (tumor-infiltrating lymphocytes; TILs) using flow cytometry and next-generation sequencing. LNLs comprised an intermediate level of the effector T cell population between peripheral blood lymphocytes (PBLs) and TILs. Significant overlap of the T cell receptor (TCR) repertoire was observed in microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) CRCs with high tumor mutation burden (TMB), although limited TCRs were shared between nonmetastatic LNs and primary tumors in microsatellite stable/MMR proficient (MSS/pMMR) CRC patients with low TMB. In line with the overlap of the TCR repertoire, an excessive LN dissection did not provide a positive impact on long-term prognosis in our MSI-H/dMMR CRC cohort (n = 130). We propose that regional LNs play an important role in antitumor immunity, particularly in MSI-H/dMMR CRCs with high TMB, requiring care to be taken regarding excessive nonmetastatic LN dissection in MSI-H/dMMR CRC patients.

Authors

Koji Inamori, Yosuke Togashi, Shota Fukuoka, Kiwamu Akagi, Kouetsu Ogasawara, Takuma Irie, Daisuke Motooka, Yoichi Kobayashi, Daisuke Sugiyama, Motohiro Kojima, Norihiko Shiiya, Shota Nakamura, Shoichi Maruyama, Yutaka Suzuki, Masaaki Ito, Hiroyoshi Nishikawa

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Figure 6

TCR repertoire among PBLs, LNLs, and TILs.

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TCR repertoire among PBLs, LNLs, and TILs. PBLs, LNLs, and TILs from 21 ...
PBLs, LNLs, and TILs from 21 CRC patients who received surgical resection were prepared, and the TCR sequencing was performed with next-generation sequencing. (A) Diversity of the TCR repertoire in PBLs, LNLs, and TILs evaluated with Shannon’s index. The top 10 TCRs are colored (left), and the summary of Shannon’s index is shown (right). (B) Correlation between TCR diversity and CCR7+CD45RA+CD8+ T cell (naive), CCR7–CD45RA–CD8+ T cell (effector memory), or PD-1+CD8+ T cell proportion. (C) Shared TCRs in TILs with PBLs or LNLs. The frequency of shared TCRs in TILs with PBLs or LNLs is shown. (D) TCR expansion from PBLs or LNLs to TILs. The frequency of shared TCRs in LNLs and TILs (left, representative patient) and the summary of shared TCR ratio (right) are shown. Shared TCRs are colored. (E) The frequency of shared TCRs in TILs with PBLs or LNLs according to MMR status. Pie charts of a representative pMMR CRC patient and a representative dMMR CRC patient (left) and the summary of shared TCR (right) are presented. Shared TCRs are colored. Means ± SDs are shown, and statistical analyses were performed using 1-way ANOVA with Bonferroni corrections in A and C, and t tests in D and E. PB, peripheral blood; dLN, distal LN; pLN, proximal LN.