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<p>The PD-L1 immune checkpoint ligates the PD-1 immune checkpoint, and antibodies against either are effective in treating selected human cancers. Although PD-L2 also ligates PD-1, αPD-L2 is little studied as cancer immunotherapy. We previously showed that αPD-L1 treated young B16-bearing mice but failed in aged. We show here that αPD-L2 fails in young B16-bearing mice but is effective in aged. αPD-L2 increases tumour-infiltrating interferon-γ<sup>+</sup> immune cell prevalence and interferon-γ production in aged but not young melanoma-bearing hosts in an unexpectedly IL-17-dependent manner. We also show improved αPD-L2 efficacy with advancing age in another tumour type, and αPD-L2-responsive tumours in young hosts, but without IL-17 dependence. The immune B16 microenvironment in aged IL-17-deficient hosts resembles that of young hosts, and exogenous IL-17 elicits αPD-L2 melanoma efficacy in young hosts, demonstrating IL-17 influence on aged immune outcomes. Mechanistic insights into age-related αPD-L2 efficacy could improve immune checkpoint blockade efficacy including in younger patients, address immune checkpoint blockade-resistant tumours and improve understanding of age effects on anti-cancer immunity.</p>

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Anti-PD-L2 immunotherapy is efficacious against melanoma in aged hosts through IL-17 and IFNγ signalling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • Carlos O. Ontiveros,
  • Myrna G. Garcia,
  • Clare E. Murray,
  • Yilun Deng,
  • Haiyan Bai,
  • Christopher Tanner,
  • Bernice Leung,
  • Xin Li,
  • Alvaro Padron,
  • Ryan M. Reyes,
  • Aravind Kancharla,
  • Kah Teong Soh,
  • Shanmugarajan Krishnan,
  • Dhan Chand,
  • Akshaya Balasubramanian,
  • Courtney Hegner,
  • Claudia V. Jakubzick,
  • Harshita B. Gupta,
  • Mary Jo Turk,
  • Mark Sundrud,
  • Jose R. Conejo-Garcia,
  • Tyler J. Curiel

摘要

The PD-L1 immune checkpoint ligates the PD-1 immune checkpoint, and antibodies against either are effective in treating selected human cancers. Although PD-L2 also ligates PD-1, αPD-L2 is little studied as cancer immunotherapy. We previously showed that αPD-L1 treated young B16-bearing mice but failed in aged. We show here that αPD-L2 fails in young B16-bearing mice but is effective in aged. αPD-L2 increases tumour-infiltrating interferon-γ+ immune cell prevalence and interferon-γ production in aged but not young melanoma-bearing hosts in an unexpectedly IL-17-dependent manner. We also show improved αPD-L2 efficacy with advancing age in another tumour type, and αPD-L2-responsive tumours in young hosts, but without IL-17 dependence. The immune B16 microenvironment in aged IL-17-deficient hosts resembles that of young hosts, and exogenous IL-17 elicits αPD-L2 melanoma efficacy in young hosts, demonstrating IL-17 influence on aged immune outcomes. Mechanistic insights into age-related αPD-L2 efficacy could improve immune checkpoint blockade efficacy including in younger patients, address immune checkpoint blockade-resistant tumours and improve understanding of age effects on anti-cancer immunity.