CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation

Ryan M. Reyes, Chenghao Zhang, Yilun Deng, Niannian Ji, Neelam Mukherjee, Alvaro S. Padron, Curtis A. Clark, Robert S. Svatek, Tyler J. Curiel

Research output: Contribution to journalArticlepeer-review

Abstract

Bladder cancer (BC) and melanoma are amenable to immune checkpoint blockade (ICB) therapy, yet most patients with advanced/metastatic disease do not respond. CD122-targeted interleukin (IL)-2 can improve ICB efficacy, but mechanisms are unclear. We tested αPD-L1 and CD122-directed immunotherapy with IL-2/αIL-2 complexes (IL-2c) in primary and metastatic bladder and melanoma tumors. IL-2c treatment of orthotopic MB49 and MBT-2 BC generated NK cell antitumor immunity through enhanced activation, reduced exhaustion, and promotion of a mature, effector NK cell phenotype. By comparison, subcutaneous B16-F10 melanoma, which is IL-2c sensitive, requires CD8+ T and not NK cells, yet we found αPD-L1 efficacy requires both CD8+ T and NK cells. We then explored αPD-L1 and IL-2c mechanisms at distinct metastatic sites and found intraperitoneal B16-F10 metastases were sensitive to αPD-L1 and IL-2c, with IL-2c but not αPD-L1, increasing CD122+ mature NK cell function, confirming conserved IL-2c effects in distinct cancer types and anatomic compartments. αPD-L1 failed to control tumor growth and prolong survival in B16-F10 lung metastases, yet IL-2c treated B16-F10 lung metastases effectively even in T cell and adaptive immunity deficient mice, which was abrogated by NK cell depletion in wild-type mice. Flow cytometric analyses of NK cells in B16-F10 lung metastases suggest that IL-2c directly boosts NK cell activation and effector function. Thus, αPD-L1 and IL-2c mediate nonredundant, immune microenvironment-specific treatment mechanisms involving CD8+ T and NK cells in primary and metastatic BC and melanoma. Mechanistic differences suggest effective treatment combinations including in other tumors or sites, warranting further studies.

Original languageEnglish (US)
Article number2006529
JournalOncoImmunology
Volume10
Issue number1
DOIs
StatePublished - 2021

Keywords

  • CD122
  • Il-2
  • NK cells
  • Preclinical
  • bladder cancer
  • immune checkpoint blockade
  • immunotherapy
  • lymphocyte activation
  • melanoma
  • metastasis
  • tumor microenvironment
  • urinary tissue-specific microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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