MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy

Abstract

Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNFα cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T-cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as a target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pretreatment expression as a biomarker to stratify melanoma patients. .

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Extracellular adenosine accumulates in tumors and suppresses cytotoxic T cells and natural killer cells (66)(67)(68). Multiple studies using syngeneic and/or spontaneous tumor models show tumor growth and metastasis is significantly reduced by genetic deletion or pharmacological blockade of CD73 or A2AR; this effect is largely due to restoring antitumor immunity (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(67)(68)(69)(70). These mice also benefit from increased chemotherapy sensitivity (36,71) and reduced angiogenesis (71,72).…”

“…CD73's potential as an immunotherapy target has advanced rapidly within the last decade (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(67)(68)(69)(70). Current studies focus on combination strategies, including ICIs, adoptive transfer, chemotherapy, and targeted therapy.…”

“…Challenges with improving efficacy include overcoming immunosuppression activity by the tumor microenvironment, unmasking pre-existing immune cell activity, and the ability to stimulate de novo immunogenicity (29). In recent years, antibodies and small molecular inhibitors against CD73 have made their way into clinical trials as an attractive target for restoring antitumor immunity (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). This review provides a summary of current literature for CD73 in GI cancers and its potential as an immunotherapy target.…”

Experimental and stochastic models of melanoma T-cell therapy define impact of subclone fitness on selection of antigen loss variants

“…The latter are included, because we reasoned that they contribute to measured tumor sizes, although they do not influence the evolution of the other cells in our mathematical model. Cytokines comprise a variety of different molecules, in particular T cell effector cytokines such as TNF-α and IFN-γ, that evoke a pro-inflammatory microenvironment promoting melanoma cell dedifferentiation and upregulation of negative immune checkpoint molecules (Chen et al, 2019;Landsberg et al, 2012;Reinhardt et al, 2017;Riesenberg et al, 2015). The state of the mathematical process…”

“…Briefly, infiltrating activated Pmel-specific CD8 + T-cells (Pmel-1 T-cells) instigated proinflammatory cytokine release which induced dedifferentiation and downregulation of the Pmel antigen in melanoma cells, which impaired immune recognition and killing (Landsberg et al, 2012;Riesenberg et al, 2015). Reciprocally, melanoma cells upregulated mesenchymal and neural crest progenitor cell traits, a finding that was recently confirmed in melanoma patients treated with ACT directed against the differentiation antigen MART-1 (Mehta et al, 2018;Reinhardt et al, 2017).…”