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Supplementary Figures 1-7, Supplementary Tables 1-8, 12 from Transient Depletion of CD4+ Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer

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posted on 2023-04-04, 01:03 authored by Hiroyasu Aoki, Satoshi Ueha, Shigeyuki Shichino, Haru Ogiwara, Kohei Shitara, Manami Shimomura, Toshihiro Suzuki, Tetsuya Nakatsura, Makiko Yamashita, Shigehisa Kitano, Sakiko Kuroda, Masashi Wakabayashi, Makoto Kurachi, Satoru Ito, Toshihiko Doi, Kouji Matsushima

Supplementary Figures 1-7 Supplementary Table 1-8, 12

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Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

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ARTICLE ABSTRACT

Antibody-mediated transient depletion of CD4+ cells enhances the expansion of tumor-reactive CD8+ T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4+ cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4+ cells promoted replacement of T-cell clones among CD4+ and CD8+ T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4+ T-cell depletion and an increase in CD8+ T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood–tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8+ overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4+ cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4+ cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer.See related Spotlight on p. 601

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