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

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...

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Autores principales:	Ryan M Reyes, Chenghao Zhang, Yilun Deng, Niannian Ji, Neelam Mukherjee, Alvaro S Padron, Curtis A Clark, Robert S Svatek, Tyler J Curiel
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	preclinical immunotherapy lymphocyte activation tumor microenvironment urinary tissue-specific microenvironment melanoma bladder cancer immune checkpoint blockade il-2 cd122 nk cells metastasis Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/6f57b3a6ecf3451ead7b6bb61c301abc
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spelling	oai:doaj.org-article:6f57b3a6ecf3451ead7b6bb61c301abc2021-11-26T11:19:49ZCD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation2162-402X10.1080/2162402X.2021.2006529https://doaj.org/article/6f57b3a6ecf3451ead7b6bb61c301abc2021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.2006529https://doaj.org/toc/2162-402XBladder 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.Ryan M ReyesChenghao ZhangYilun DengNiannian JiNeelam MukherjeeAlvaro S PadronCurtis A ClarkRobert S SvatekTyler J CurielTaylor & Francis Grouparticlepreclinicalimmunotherapylymphocyte activationtumor microenvironmenturinary tissue-specific microenvironmentmelanomabladder cancerimmune checkpoint blockadeil-2cd122nk cellsmetastasisImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	preclinical immunotherapy lymphocyte activation tumor microenvironment urinary tissue-specific microenvironment melanoma bladder cancer immune checkpoint blockade il-2 cd122 nk cells metastasis Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	preclinical immunotherapy lymphocyte activation tumor microenvironment urinary tissue-specific microenvironment melanoma bladder cancer immune checkpoint blockade il-2 cd122 nk cells metastasis Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ryan M Reyes Chenghao Zhang Yilun Deng Niannian Ji Neelam Mukherjee Alvaro S Padron Curtis A Clark Robert S Svatek Tyler J Curiel CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation
description	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.
format	article
author	Ryan M Reyes Chenghao Zhang Yilun Deng Niannian Ji Neelam Mukherjee Alvaro S Padron Curtis A Clark Robert S Svatek Tyler J Curiel
author_facet	Ryan M Reyes Chenghao Zhang Yilun Deng Niannian Ji Neelam Mukherjee Alvaro S Padron Curtis A Clark Robert S Svatek Tyler J Curiel
author_sort	Ryan M Reyes
title	CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation
title_short	CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation
title_full	CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation
title_fullStr	CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation
title_full_unstemmed	CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation
title_sort	cd122-targeted interleukin-2 and αpd-l1 treat bladder cancer and melanoma via distinct mechanisms, including cd122-driven natural killer cell maturation
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/6f57b3a6ecf3451ead7b6bb61c301abc
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CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation

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