Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.
Journal of immunology (Baltimore, Md. : 1950). 2024 May 17 [Epub ahead of print]
Tokiyoshi Tanegashima, Masaki Shiota, Nobuhiro Fujiyama, Shintaro Narita, Tomonori Habuchi, Genshiro Fukuchi, Dai Takamatsu, Yoshinao Oda, Hideaki Miyake, Masayuki Takahashi, Mototsugu Oya, Norihiko Tsuchiya, Naoya Masumori, Hideyasu Matsuyama, Wataru Obara, Nobuo Shinohara, Kiyohide Fujimoto, Masahiro Nozawa, Kojiro Ohba, Chikara Ohyama, Katsuyoshi Hashine, Shusuke Akamatsu, Tomomi Kamba, Koji Mita, Momokazu Gotoh, Shuichi Tatarano, Masato Fujisawa, Yoshihiko Tomita, Shoichiro Mukai, Keiichi Ito, Shoji Tokunaga, Masatoshi Eto
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan., Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan., Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan., Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Department of Urology, Keio University School of Medicine, Tokyo, Japan., Department of Urology, Faculty of Medicine, Yamagata University, Yamagata, Japan., Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan., Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan., Department of Urology, Iwate Medical University School of Medicine, Iwate, Japan., Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan., Department of Urology, Nara Medical University, Kashihara, Japan., Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan., Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan., Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan., Department of Urology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan., Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan., Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto Japan., Department of Urology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan., Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan., Department of Urology and Molecular Oncology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan., Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan., Department of Urology, National Defense Medical College, Saitama, Japan., Medical Information Center, Kyushu University Hospital, Fukuoka, Japan.