Abstract
Inherent intermediate- to low-affinity T-cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T-cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T-cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering reinstated Th1 function in tumor-infiltrating lymphocytes that had been functionally disabled in the human renal cell carcinoma environment without unleashing undesired Th2 cytokines or IL10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFNγ compared with T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T-cell function make it an attractive tool for ATT. Cancer Res; 77(13); 3577-90. ©2017 AACR.
Highlights
Magnitude, quality, and functional polarization of an immune response are crucial for the control of many diseases, including cancer
PD-1:28 chimeric receptor expression depends on the origin of the transmembrane domain
Consistent with the PD-L1 expression on TCR53 target cells, TCR53-T cells derived strong benefit from PD-1:28tm engineering with 1.4- to 2.5-fold improvement of IFNg secretion (Fig. 4E). These results indicate that T cells will benefit more from PD-1:28tm engineering in tumor milieus where PD-L1 is highly expressed
Summary
Quality, and functional polarization of an immune response are crucial for the control of many diseases, including cancer. (1) and checkpoint inhibition [2], which achieve remarkable tumor regressions even in patients who have failed previous treatments. Despite these successes, immunotherapeutic concepts need to be improved as no or low response is still a frequent outcome. At least two major impediments have been identified that impinge upon achieving this prerequisite: inherent intermediate- to low-affinity T-cell receptors (TCR) of antitumor T cells that may not mount a successful tumor-specific response [3, 4], and functional inactivation of T cells in the tumor milieu [5,6,7,8]
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