Adenosine-Axis Blockade and Adoptive T Cell Therapy
There are two main approaches to ACT. Either autologous tumor-reactive T cells are expanded from tumor biopsies prior to patient re-infusion [i.e., tumor infiltrating lymphocyte (TIL) therapy], or peripheral blood T cells are gene-engineered to express a tumor-specific T cell receptor (TCR), or a so-called chimeric antigen receptor (CAR; a fusion protein that links scFv-mediated tumor antigen-binding with intracellular endo-domains associated with T cell activation). Cancer patients are typically lymphodepleted prior to ACT, and following infusion they receive high doses of IL-2, both of which support T cell engraftment (426). TIL therapy has achieved robust and durable responses in advanced melanoma patients, while CAR therapy targeting CD19 has yielded unprecedented clinical responses against a variety of advanced, treatment-refractory B cell malignancies (118, 427, 428).
Synergy has been demonstrated between strategies limiting adenosine production blockade and ACT within tumor-bearing mice. Indeed, ACT confers increased control of tumors lacking CD73 expression (388) and dual therapy of ACT and pharmacologic or mAb-mediated inhibition of CD73 was more robust than single treatments at augmenting tumor control and overall survival (378). Mechanistically, pharmacologic inhibition of CD73 potentiated the anti-tumor efficacy of ACT at least by boosting the homing of the adoptively transferred tumor-specific T cells at the tumor sites (378). Likewise, respiratory hyperoxia in mice increased the ability of adoptively transferred T cells to curb primary tumor expansion and metastasis formation by augmenting their capacity to accumulate in the TME and produce IFNγ (293).
Similarly, A2AR deficiency (402) or siRNA-mediated suppression of A2AR and A2BR expression (38) on the surface of adoptively transferred T cells leads to enhanced prevention of metastatic spreading (38, 402) and improved survival of tumor-bearing mice (38). Several groups have validated these observations by demonstrating that ACT and concomitant administration of A2AR antagonists is superior to single treatments in terms of decreasing tumor growth (135, 396), hindering metastasis formation (38, 402) and ultimately improving survival (135, 388, 396, 402). Interestingly, others claim that A2AR antagonism improves the efficacy of adoptively transferred CAR+ T cells only if PD1 ICB is co-administered (135). In terms of mechanisms, concomitant A2AR antagonism not only increases intra-tumoral presence of adoptively transferred T cells (396) but also elevates their activation status. In particular, when A2AR antagonists were co-administered, tumor-derived, adoptively transferred or endogenous CD44+ CD8+ T cells, exhibit heightened expression levels of T-bet, 4-1BB, and CD69 (396) while demonstrating increased capacity to produce IFNγ and TNFα (135, 396, 402).