PD-1 Blockade on Tumor Microenvironment-Resident ILC2s Promotes TNF-α Production and Restricts Progression of Metastatic Melanoma.

Emily Howard,Jacob D Painter,Pedram Shafiei-Jahani,Marshall Fung,Benjamin P Hurrell,Parkash S Gill,Doumet Georges Helou,Christine Quach,Pejman Soroosh,Arlene H Sharpe,Omid Akbari

doi:10.3389/fimmu.2021.733136

Emily Howard, Jacob D Painter + Show 9 more

Open Access

https://doi.org/10.3389/fimmu.2021.733136

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Abstract

While pulmonary ILC2s represent one of the major tissue-resident innate lymphoid cell populations at steady state and are key drivers of cytokine secretion in their occupational niche, their role in pulmonary cancer progression remains unclear. As the programmed cell death protein-1 (PD-1) plays a major role in cancer immunotherapy and immunoregulatory properties, here we investigate the specific effect of PD-1 inhibition on ILC2s during pulmonary B16 melanoma cancer metastasis. We demonstrate that PD-1 inhibition on ILC2s suppresses B16 tumor growth. Further, PD-1 inhibition upregulates pulmonary ILC2-derived TNF-α production, a cytotoxic cytokine that directly induces cell death in B16 cells, independent of adaptive immunity. Together, these results highlight the importance of ILC2s and their anti-tumor role in pulmonary B16 cancer progression during PD-1 inhibitory immunotherapy.

Highlights

Melanoma is a highly aggressive form of cancer that spreads from primary skin sites to various organs throughout the human body [1, 2]
We first assessed the effect of B16 melanoma tumors on ILC2 programmed death-1 receptor (PD-1) expression
The percentage of PD-1+ ILC2s significantly increased after B16 inoculation, from a mean of 15% PD-1+ ILC2s to 60% PD-1+ ILC2s, demonstrating B16 melanoma induces PD-1 expression on pulmonary ILC2s and may subsequently alter anti-tumor effector function (Figure 1D)

Summary

Introduction

Melanoma is a highly aggressive form of cancer that spreads from primary skin sites to various organs throughout the human body [1, 2]. While effective treatment is attainable if diagnosed at the early stages, 20% of melanomas diagnosed in advanced stages resist treatment [3, 4]. Pulmonary metastasis is the most common progression in the late stages of cancer diagnosis [5]. According to the World Health Organization, over 106,000 melanomas were diagnosed, and 7,000 new fatalities occurred in the United States in 2020. While the rates of melanoma diagnosis continue to be alarming, molecularly targeted approaches, including inhibition of immune checkpoints such as programmed death-1 receptor (PD-1) have significantly improved patient outcomes over the last decade. A Food and Drug Administration-approved antibody directed at PD-1 inhibition enhanced median overall

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