Scholarlink

Background <p>The combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects.</p> Methods <p>We thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy.</p> Results <p>We found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the tumor microenvironment (TME) better for ICI treatments. Triple combination of chemotherapy, innate agonists, and ICIs is superior to single modalities or double modalities in antitumor efficacies. Adding chemotherapy to innate agonists enhances the infiltration of overall CD8<sup>+</sup> T cells and the memory cytotoxic subtype. NLRP3 agonist has a less effect than STING agonist on driving the T cell exhaustion. Adding chemotherapy to innate agonists enhances the infiltration of dendritic cells (DCs) in the tumors and CD86<sup>+</sup> mature DCs in tumor draining lymph nodes. RNA sequencing analysis of the pancreatic tumors demonstrates the role of the combination of STING/NLRP3 agonist and chemotherapy, but not either treatment modality alone, in upregulating the T cell activation signaling. The NLRP3 agonist-mediated T cell activation is likely through regulating the nitrogen metabolism pathways.</p> Conclusion <p>This study supports the clinical testing of both STING and NLRP3 agonists, respectively, in combination with chemotherapy to sensitize PDAC patients for ICI treatments.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Chemotherapy in synergy with innate immune agonists enhances T cell priming for checkpoint inhibitor treatment in pancreatic cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月27日

查看全文
  • Nan Niu,
  • Keyu Li,
  • Junke Wang,
  • Vanessa Funes,
  • Birginia Espinoza,
  • Pan Li,
  • Jianxin Wang,
  • Melissa Lyman,
  • Mengni He,
  • Brian Herbst,
  • Michael Wichroski,
  • Ruslan Novosiadly,
  • Sami Shoucair,
  • Yiping Mou,
  • Lei Zheng

摘要

Background

The combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects.

Methods

We thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy.

Results

We found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the tumor microenvironment (TME) better for ICI treatments. Triple combination of chemotherapy, innate agonists, and ICIs is superior to single modalities or double modalities in antitumor efficacies. Adding chemotherapy to innate agonists enhances the infiltration of overall CD8+ T cells and the memory cytotoxic subtype. NLRP3 agonist has a less effect than STING agonist on driving the T cell exhaustion. Adding chemotherapy to innate agonists enhances the infiltration of dendritic cells (DCs) in the tumors and CD86+ mature DCs in tumor draining lymph nodes. RNA sequencing analysis of the pancreatic tumors demonstrates the role of the combination of STING/NLRP3 agonist and chemotherapy, but not either treatment modality alone, in upregulating the T cell activation signaling. The NLRP3 agonist-mediated T cell activation is likely through regulating the nitrogen metabolism pathways.

Conclusion

This study supports the clinical testing of both STING and NLRP3 agonists, respectively, in combination with chemotherapy to sensitize PDAC patients for ICI treatments.