Targeting Cyclin D-CDK4/6 Sensitizes Immune-Refractory Cancer by Blocking the SCP3–NANOG Axis

Abstract

Immunoediting caused by antitumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOG cancer stem cell-like cells. In this study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immunoedited cells and upregulates NANOG by hyperactivating the cyclin D1-CDK4/6 axis. The SCP3-cyclin D1-CDK4/6 axis was preserved across various types of human cancer and correlated negatively with progression-free survival of cervical cancer patients. Targeting CDK4/6 with the inhibitor palbociclib reversed multiaggressive phenotypes of SCP3 immunoedited tumor cells and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3 immune-refractory cancer. These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3 immune-refractroy cancer. .

To Cycle or Fight—CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity

“…Oh and colleagues studied a highly immune-refractory cancer and found that synaptonemal complex protein 3 (SCP3) is overexpressed in immune-edited cancer cells and upregulates the pluripotency transcriptional factor NANOG by hyperactivation of the Cyclin D-CDK4/6 axis. In this model, the combination of palbociclib together with adoptive cytotoxic cell transfer showed considerable therapeutic efficacy, suggesting a niche role for CDK4/6 inhibitors in immunotherapy combinations in the resistant/refractory setting (79).…”

Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes

“…3, B and C), indicating an important role of CXCL10 in the property mediated by TCTP. For the TCTP-mediated anti-apoptotic response to CTLs, we noted an increase in anti-apoptotic protein MCL-1, a signature molecule rendering tumor cells resistant to CTLinduced killing in previous studies 12,14,19 , in CT26 P3 cells as well as CT26 TCTP cells, relative to P0 or CT26-no cells, respectively (Supplemental Fig. 5C and Fig.…”

“…Accumulating evidence has demonstrated that consistent and evolving reciprocal interaction between the anti-cancer immune system and tumor cells confers intrinsic-and/or extrinsic-resistance to immunotherapy. In the immunoediting process, CTL-mediated immune selection drives the adaptation of tumor cells to host immune surveillance, thereby contributing to generating tumor cells with intrinsicresistance to CTL attack 12,14 . Conversely, tumor cells repress anti-tumor immunity through impairing TIL recruitment to the tumor and effector function, known as extrinsic-resistance 15,17,55 .…”

“…Previously, we found that CTL-mediated immune selection promoted the enrichment of a subset of cells with immune-refractory properties 12,14 . As tumor antigen-speci c CTLs are key effectors in anti-PD-L1 therapy, we reasoned that increased TCTP expression under anti-PD-L1 therapy is due to immune selection imposed by CTLs.…”

“…Decreased T cell tra cking to tumors appears in low immunotherapy responses compared to T cellrecruited tumors in patients 10,11 . Besides, even if T cells in ltrate a tumor, the intrinsic resistance of tumor cells to CTL-mediated killing could be another obstacle [12][13][14] . Thus, controlling both T cell tra cking to the tumor and the anti-apoptotic properties of tumor cells to CTLs is needed to improve the effectiveness of T cell-mediated therapy.…”