Immune Checkpoint Assay
Schematic & images adapted from reference (1) Jenkins et al.
Despite the success of immune checkpoint blockade (ICB) therapies in recent years, they are limited to a minority of patients due to innate (primary) resistance. Combination therapy that uses dual ICB, anti-PD-1 and anti-CTLA4 has shown promising results in advanced melanoma as compared to either monotherapy. As the number of combination therapies is ever increasing, there is a need for an ICB assay that can accurately predict the efficacy of these therapies in the preclinical and clinical settings in a timely manner. Murine-derived/patient-derived organotypic tumor spheroids (MDOTS/PDOTS) developed by Jenkins et al in AIM 3D cell culture devices address this need (see reference (1)). MDOTS/PDOTS isolated from mouse and patient tumors retain the autologous immune cells and matrixes which are critical for the ICB response. The preserved tumor microenvironment ensures that the tumor-immune and cell-matrix interactions are not compromised in this ex vivo assay. MDOTS/PDOTS not only recapitulate the in vivo immune response (as shown below), but also yield the results within a week which can help accelerate the drug discovery process.
MDOTS cultured in AIM chips capture the in vivo responses of PD-1 sensitive MC38 and PD-1 resistant B16F10 under PD-1 treatment. The MC38 MDOTS respond to PD-1 treatment in a dose dependent manner while the B16F10 MDOTS do not respond to the PD-1 treatment at all dosages.
Data & images adapted from reference (1) Jenkins et al.
MDOTS cultured in AIM chips predict the effectiveness of novel combination therapies (PD-L1 blockade + TBK1 inhibitor), as evidenced by in vivo tests using CT26 mice. Neither PD-L1 blockade nor TBK1 inhibitor alone is effective in causing cancer cell death in the CT26 MDOTS. Nevertheless, the combination of PD-L1 blockade & TBK1 inhibitor increases cancer cell death in the MDOTS, and also prolongs the survival rate of CT26 mice.
Images adapted from reference (1) Jenkins et al.
Please refer to reference (4) by Aref et al for details on conducting the immune checkpoint assay.
Users can submit their protocols to be referenced in this section and given due credit.
- *Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Jenkins RW, Aref AR, Lizotte PH, Ivanova E, Stinson S, Zhou CW, ... Barbie DA. Cancer Discov. 2017 Nov 3. pii: CD-17-0833. doi: 10.1158/2159-8290.CD-17-0833.
- *CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation. Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, ... Wong KK. Cancer Discov. 2017 Nov 3. pii: CD-17-0915. doi: 10.1158/2159-8290.CD-17-0915.
- *Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Cañadas I, Thummalapalli R, Kim JW, Kitajima S, Jenkins RW, Christensen CL... Barbie DA. Nature Medicine 23 July 2018 doi.org/10.1038/s41591-018-0116-5
- *3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Aref AR, Campisi M, Ivanova E, Portell A, Larios D, Piel BP... Jenkins RW. Lab on a Chip, 5 Sep 2018, DOI: 10.1039/C8LC00322J
- *Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Kitajima S, Ivanova E, Guo S, Yoshida R, Campisi M... Barbie DA. Cancer Discov. Epub 8 Oct 2018 DOI: 10.1158/2159-8290.CD-18-0689
- *BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non–Small Cell Lung Cancer. Adeegbe DO, Liu SW, Hattersley MM, Bowden M, ZhouCW, Li S... Wong KK. Cancer Immunol Res; 6(10); 1234–45. Epub 7 Aug 2018 DOI: 10.1158/2326-6066.CIR-18-0077
- *Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW... Hacohen N. Cell vol 175, issue 4, P998-1013.E20, November 01, 2018. https://doi.org/10.1016/j.cell.2018.10.038
- *Molecular recalibration of PD-1+ antigen-specific T cells from blood and liver. Otano I, Escors D, Schurich A, Singh H, Robertson F, Davidson BR... Maini MK. Molecular Therapy (7 Nov 2018), doi: 10.1016/j.ymthe.2018.08.013.
- *RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. Wang W, Marinis JM, Beal AM, Savadkar S, Wu Y, Khan M... Miller G. Cancer Cell 34, 757–774, November 12, 2018. https://doi.org/10.1016/j.ccell.2018.10.006