Prospects of Combinatorial Approach Involving ICD Induction and Adenosine A2A Receptor Pathway Inhibition to Improve Cancer Immunotherapy

The purpose of this review is to discuss and summarize the prospects of combinatorial approach involving immunogenic cell death induction and immunosuppressive adenosine A2A receptor pathway inhibition in enhancing anti-tumor immunity. Majority of chemotherapeutic agents can elicit antitumor immunity and modulate the composition, density, function, and distribution of Tumor Infiltrating Lymphocytes (TILs), to influence differential therapeutic responses and prognosis in cancer patients. Accumulating evidence indicates that the clinical success of these agents not only dependents on their cytotoxic activity but also by the enhancement of pre-existing immunity. Over expression of CD39 or CD73 enzymes has been implicated in limiting the ICD caused by chemotherapeutic agents like anthracyclines and oxaliplatin. Conversion of ATP released by chemotherapeutic drugs into adenosine dampens its capacity to attract antigen presenting cells including Dendritic Cells (DC) into the proximity of dying and dead cells. In addition, released adenosine exits potent immunosuppressive activities on different immune cells through A2A receptors in the TME and contributes to the resistance against chemotherapy. Resistance either intrinsic or acquired is the major hurdle for most of the therapeutic interventions. In order to enhance immunogenic cell death by chemotherapeutic agents, it has become clear that blockade of adenosine production or its signaling need to be specifically targeted as they represent highly resistant mechanisms. Given the prominent role of adenosine mediated immune suppression and resistance to ICD induction in TME, combination strategies that involve ICD induction and adenosine signaling blockade are further warranted.