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Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including
Ryan M Reyes1,2, Chenghao Zhang2,3, Yilun Deng2
1South Texas Medical Scientist Training Program, University of Texas Health San Antonio, San Antonio, TX, USA.
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.
Insights
Immune checkpoint blockade (ICB) combined with IL-2 therapy shows promise for bladder cancer and melanoma. This study reveals distinct immune mechanisms involving CD8+ T and NK cells, suggesting tailored combination strategies for improved cancer treatment.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Immune checkpoint blockade (ICB) therapy is effective for bladder cancer (BC) and melanoma, but response rates are limited in advanced/metastatic disease.
- Interleukin (IL)-2, when targeted to CD122, can enhance ICB efficacy, yet its precise mechanisms remain unclear.
- Understanding the interplay between ICB and IL-2 in different cancer types and metastatic sites is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the mechanisms of action for αPD-L1 and CD122-targeted IL-2 complexes (IL-2c) in primary and metastatic bladder cancer and melanoma.
- To elucidate the roles of CD8+ T cells and NK cells in mediating the antitumor effects of these immunotherapies.
- To determine if IL-2c exhibits conserved effects across different cancer types and anatomical locations.
Main Methods:
- Utilized orthotopic MB49 and MBT-2 bladder cancer models and subcutaneous/intraperitoneal/lung B16-F10 melanoma models.
- Administered αPD-L1 and IL-2c immunotherapy, alone and in combination.
- Employed flow cytometry to analyze immune cell populations (NK cells, CD8+ T cells) and their activation/exhaustion status.
- Assessed tumor growth, survival, and response in immunocompetent and immunodeficient mouse models.
Main Results:
- IL-2c promoted NK cell antitumor immunity in bladder cancer by enhancing activation and effector function.
- αPD-L1 efficacy in melanoma required both CD8+ T and NK cells, while IL-2c primarily relied on CD8+ T cells in subcutaneous models.
- IL-2c demonstrated conserved effects on NK cell function in both bladder cancer and melanoma, across different metastatic sites.
- αPD-L1 was ineffective against lung metastases, whereas IL-2c showed significant efficacy, even in the absence of adaptive immunity, highlighting NK cell dependence.
Conclusions:
- αPD-L1 and IL-2c exert distinct, immune microenvironment-specific mechanisms involving CD8+ T and NK cells in bladder cancer and melanoma.
- IL-2c directly enhances NK cell activation and effector function, offering a potent therapeutic strategy, particularly for lung metastases.
- These mechanistic differences support the development of tailored combination immunotherapies for various cancers and metastatic sites.
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