Identification of a novel resistant mechanism for agonistic costimulatory therapy

Project: Research project

Project Details


Recent approval of YERVOY™ (ipilimumab, anti-CTLA-4) and Keytruda (pembrolizumab, anti-PD-1)
by the US FDA marks the validation of immunotherapy for advanced metastatic melanoma patients, which has led to a renaissance in
melanoma therapeutics using immunostimulatory monoclonal antibodies (mAbs) that enhance immune responses. In addition to
blocking immune-inhibitory molecules (e.g. CTLA-4 and PD-1), activating immune co-stimulatory pathways (e.g. OX40, CD137 and
CD40) to potentiate antitumor immune responses is a promising approach (1, 2). OX40 (TNFRSF4, CD134), a member of the tumor
necrosis factor receptor (TNFR) superfamily is expressed on activated both CD4+ and CD8+ T cells (3). As OX40 engagement can
promote T cell proliferation, survival, effector function and memory (4-7), agonistic mAbs and/or soluble forms of OX40L have been
used successfully in a variety of preclinical tumor models and clinical trials (1). As a monotherapy, OX40 engagement has been
unable to provide adequate antitumor immunity in established and more clinically relevant poorly immunogenic tumors, while being
effective in eradicating primarily small immunogenic tumors (1), calling for identification of resistance mechanisms. It is conceivable
that an immunosuppressive tumor microenvironment results in resistance to agonistic anti-OX40 therapy.
CD73-mediated adenosinergic effects are now considered one of the most important immunosuppressive pathways in the tumor (8-
13). We and others have demonstrated the pivotal role of tumor and host CD73-mediated adenosinergic effects on tumor growth and
metastasis (14-17), and up-regulation of CD73 expression has been also observed in a broad spectrum of solid cancers including
melanoma (8). We further verified the antitumor effect of anti-CD73 administration in a more clinically relevant melanoma model, i.e.
the Braf-activated/Pten-deficient mouse model (18, 19). To this end, we examined the inhibitory role of CD73 in the context of
therapies targeting co-stimulatory molecule OX40 and set out to determine whether CD73-mediated adenosinergic effects are a crucial
resistant mechanism for agonistic anti-OX40 mAb therapy. Our preliminary data showed that CD73-deificient mice treated with
agonistic anti-OX40 mAb completely rejected B16 melanoma growth when compared with WT mice, highlighting the importance of
an inhibitory role for host-derived CD73. To explore the therapeutic relevance, we combined anti-OX40 and anti-CD73 mAb to treat
mice with established poorly immunogenic B16 melanoma. This combination therapy induced tumor regression associated with
enhanced antitumor CD8+ T cell responses and decreased number of both peripheral and tumor-infiltrating Treg cells leading to a
favorable T effector/ T reg cell ratio. In contrast, neither anti-OX40 nor anti-CD73 monotherapy is effective to control the growth of
established melanoma. Along these lines, we hypothesize that CD73-mediated adenosinergic effects are a novel crucial resistant
mechanism for agonistic anti-OX40 mAb therapy.
Effective start/end date9/1/158/31/16


  • American Association of Immunologists, Inc. (AMGT-6/25/15)


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.