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Multicenter Study
. 2024 Jul 1;213(1):23-28.
doi: 10.4049/jimmunol.2300308.

Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study

Tokiyoshi Tanegashima  1 , Masaki Shiota  1 , Nobuhiro Fujiyama  2 , Shintaro Narita  3 , Tomonori Habuchi  3 , Genshiro Fukuchi  1   4 , Dai Takamatsu  1   4 , Yoshinao Oda  4 , Hideaki Miyake  5 , Masayuki Takahashi  6 , Mototsugu Oya  7 , Norihiko Tsuchiya  8 , Naoya Masumori  9 , Hideyasu Matsuyama  10 , Wataru Obara  11 , Nobuo Shinohara  12 , Kiyohide Fujimoto  13 , Masahiro Nozawa  14 , Kojiro Ohba  15 , Chikara Ohyama  16 , Katsuyoshi Hashine  17 , Shusuke Akamatsu  18 , Tomomi Kamba  19 , Koji Mita  20 , Momokazu Gotoh  21 , Shuichi Tatarano  22 , Masato Fujisawa  23 , Yoshihiko Tomita  24 , Shoichiro Mukai  25 , Keiichi Ito  26 , Shoji Tokunaga  27 , Masatoshi Eto  1
Affiliations
Multicenter Study

Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study

Tokiyoshi Tanegashima et al. J Immunol. .

Abstract

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.

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Conflict of interest statement

H.M. received honoraria from Ono Pharmaceutical. M.T. received honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. M.O. received honoraria from Pfizer, Novartis, Bayer, MSD, Eisai, Ono Pharmaceutical, Bristol-Myers Squibb, Takeda Pharmaceutical and Merck Biopharma. N.T. received honoraria from Pfizer, Novartis, MSD, Eisai, Bristol-Myers Squibb, Takeda Pharmaceutical, and Merck Biopharma and support for attending meetings from Merck Biopharma. N.M. received honoraria from MSD, Bristol-Myers Squibb, Takeda Pharmaceutical, and Ono Pharmaceutical. H.M. received grants from Janssen Pharma, Takeda Pharmaceutical, Baxter, KyowaKirin, and Sanofi and honoraria from Janssen Pharma, AstraZeneca, Merck Biopharma, Bayer, Astellas Pharma, and Chugai. W.O. received honoraria from Ono Pharmaceutical, Merck Biopharma, Takeda Pharmaceutical, and Astellas Pharma. N.S. received grants from Ono Pharmaceutical, honoraria from Ono Pharmaceutical and Bristol-Myers Squibb, and support for attending meetings from Ono Pharmaceutical and Bristol-Myers Squibb. M.N. received honoraria from Takeda Pharmaceutical. S.A. received grants from Astellas Pharma, AstraZeneca, and Tosoh and honoraria from Janssen Pharma, AstraZeneca, Bayer, Astellas Pharma, Sanofi, and Takeda Pharmaceutical. T.K. received honoraria from AstraZeneca and Merck Biopharma. M.E. received grants from Ono Pharmaceutical and honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. All other authors have no financial conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
Distributions of the HED for each HLA-I and HLA-II locus. (A) HLA-A (n = 222 patients; median = 9.76) versus HLA-B (n = 221 patients; median = 7.41; p = 0.2649); HLA-A versus HLA-C (n = 222 patients; median = 4.66; p < 0.0001); HLA-B versus HLA-C (p < 0.0001). (B) HLA-DQB1 (n = 222 patients; median = 10.02) versus HLA-DRB1 (n = 222 patients; median = 10.33; p = 0.0071). One-way ANOVA with Tukey multiple comparison test (A) and Mann–Whitney U test (B) were used.
FIGURE 2.
FIGURE 2.
Kaplan–Meier survival analysis of CSS, stratified by the HED at each HLA locus. CSS stratified by the HED at the HLA-A (A), HLA-B (B), HLA-C (C), HLA-DQB1 (D), or HLA-DRB1 (E) loci. The threshold of the HED at each HLA locus was defined as the median. High was defined as having a value greater than the median, and low was defined as having a value less than or equal to the median. Survival analysis was performed using the Kaplan–Meier method and the log-rank test.
FIGURE 3.
FIGURE 3.
The association of the HED at the HLA-B locus with tumor-infiltrating CD8+ and CD4+ cells. (A) The correlation with the HED at the HLA-B locus and the number of CD8+ cell infiltration in the tumor (n = 15). (B) The correlation with the HED at the HLA-B locus and the number of CD4+ cell infiltration in the tumor (n = 15). (C) Representative CD8+ and CD4+ immunostaining images in the tumors from patients with high and low HED at the HLA-B locus. HPF, high-power field. Scale bar, 100 μm.
See this image and copyright information in PMC

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