Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Alterations in Intratumoral Immune Response Before and Early-on-Treatment of Nivolumab in Unresectable Advanced or Recurrent Gastric Cancer

Yasuyoshi Sato
,
Hiroharu Yamashita
,
Yukari Kobayashi
ORCID logo ,
Koji Nagaoka
ORCID logo ,
Tetsuro Hisayoshi
,
Takuya Kawahara
ORCID logo ,
Akihiro Kuroda
,
Noriyuki Saito
,
Ryohei Iwata
,
Yasuhiro Okumura
,
Koichi Yagi
,
Susumu Aiko
,
Sachiyo Nomura
ORCID logo ,
Kazuhiro Kakimi
* ORCID logo ,
Yasuyuki Seto
ORCID logo
Version 1 : Received: 17 October 2023 / Approved: 18 October 2023 / Online: 19 October 2023 (03:29:48 CEST)

A peer-reviewed article of this Preprint also exists.

Sato, Y.; Yamashita, H.; Kobayashi, Y.; Nagaoka, K.; Hisayoshi, T.; Kawahara, T.; Kuroda, A.; Saito, N.; Iwata, R.; Okumura, Y.; Yagi, K.; Aiko, S.; Nomura, S.; Kakimi, K.; Seto, Y. Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer. Int. J. Mol. Sci. 2023, 24, 16602. Sato, Y.; Yamashita, H.; Kobayashi, Y.; Nagaoka, K.; Hisayoshi, T.; Kawahara, T.; Kuroda, A.; Saito, N.; Iwata, R.; Okumura, Y.; Yagi, K.; Aiko, S.; Nomura, S.; Kakimi, K.; Seto, Y. Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer. Int. J. Mol. Sci. 2023, 24, 16602.

Abstract

Background: We investigated the tumor immune response in gastric cancer patients receiving third line nivolumab monotherapy to identify immune-related biomarkers for better patient se-lection. Methods: Nineteen patients (10 males, median age 67 years) who received nivolumab as a third or later line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. Results: DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR, OS, PFS) to previous trials. Individual immunograms showed no significant changes before and ear-ly-on-treatment, nor consistent alterations among DCB cases. The intratumoral immune response was suppressed by previous treatments in most third or later line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in on-treatment tumors, but clonal re-placement did not impact efficacy. High T cells/Tregs ratios and a low UV radiation response gene signature were linked to DCB and treatment response. Conclusions: This study emphasizes the tumor immune response's importance in nivolumab ef-ficacy for gastric cancer. High T cells/Tregs ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. Larger cohort validation is crucial to optimize immune checkpoint inhibitors in gastric cancer treatment.

Keywords

gastric cancer; Nivolumab; immune response; tumor microenvironment; RNA-Seq

Subject

Medicine and Pharmacology, Other

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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