Lung cancer kills more people than any other type of cancer, including more than 130,000 people each year in
the United States. Non-small cell lung cancer (NSCLC) is the most common subtype (82% of all lung cancers)
and can arise from squamous or non-squamous lung epithelial cells. Combination treatment with immunotherapy
(i.e., monoclonal antibodies targeted to PD-1 or PD-L1) plus concurrent chemotherapy (usually including cisplatin
or carboplatin) is now part of the standard of care for many patients with NSCLC. Although in lab-based studies,
chemotherapy has some effects that are expected to enhance the efficacy of immunotherapies, whether
chemotherapy can also have paradoxical negative effects that diminish immunotherapy efficacy is not well
understood at present. Based on our preliminary data, we propose to investigate how cisplatin, a chemotherapy
commonly used to treat NSCLC, creates an immunosuppressive tumor microenvironment (TME) that limits the
anti-tumor activity of anti-PD-1 immunotherapy. Specifically, we hypothesize the following steps: (a) cisplatin
induces prostaglandin E2 (PGE2) production in tumor cells; (b) PGE2 leads to upregulation of CD73 enzyme on
the surface of monocytic myeloid-derived suppressor cells (M-MDSCs); (c) CD73 catalyzes the production of
extracellular adenosine from AMP (derived from ATP released from dying cells); and (d) adenosine inhibits the
activation of effector T cells within the tumor microenvironment (TME) and thus limits the efficacy of chemo-
immunotherapy. Furthermore, we propose a novel therapeutic strategy for overcoming this adenosine-mediated
immunosuppression and sensitizing tumors to chemo-immunotherapy, whereby co-treatment with recombinant
polyethylene glycol-conjugated adenosine deaminase enzyme (PEG-ADA) will convert immunosuppressive
adenosine into immunostimulatory inosine. In Specific Aim 1 of this project, we will test our predictions about the
key cellular and molecular players in this pathway, including cisplatin-induced PGE2 secretion, CD73 expression
on M-MDSC, adenosine production and suppression of anti-tumoral T cell activity. We will use a variety of in vivo
systems that provide a faithful representation of human NSCLC, including an orthotopic murine lung cancer
model and humanized mice with patient-derived xenografts (PDX). In Specific Aim 2, we will test the
effectiveness of selectively deleting CD73 in M-MDSCs or co-treating with PEG-ADA as approaches to increase
the anti-tumor/immunostimulatory activities of chemo-immunotherapy (anti-PD-1 + cisplatin) in transgenic mouse
models of non-squamous and squamous NSCLC. We will also examine tumor samples from NSCLC patients
who have progressed on anti-PD-1/chemotherapy for correlative evidence of this novel mechanism. Completion
of these aims will identify novel and actionable immunosuppressive mechanisms that mediate relapse and
therapeutic resistance in metastatic NSCLC patients. Our studies will establish adding PEG-ADA (a drug that is
FDA-approved for a non-cancer indication) to standard chemo-immunotherapy as a promising strategy that can
be quickly translated into improved NSCLC treatment regimens.
