Cancer Vaccination Drives Nanog-Dependent Evolution of Tumor Cells toward an Immune-Resistant and Stem-like Phenotype

Abstract

Due to the exquisite specificity and potency of the immune system, vaccination is in theory the most precise and powerful approach for controlling cancer. However, current data from clinical trials indicate that vaccination rarely yields significant benefits for cancer patients in terms of tumor progression and long-term survival. The poor clinical outcomes of vaccination are primarily caused by mechanisms of immune tolerance, especially within the tumor microenvironment. Here we report that vaccination drives the evolution of tumor cells towards an immune-resistant and stem-like phenotype that promotes tumor growth and nullifies the cytotoxic T lymphocyte (CTL) response. The emergence of this phenotype required the transcription factor Nanog, which is induced as a consequence of immune selection. Nanog expression enhanced the stem-like features of tumor cells and protected them from killing by tumor-reactive CTLs. Delivery of siNanog into tumor-bearing mice rendered the tumor vulnerable to immune surveillance and strongly suppressed its growth. Together, our findings demonstrate tumor adaptation to vaccination through gain of an immune-resistant, stem-like phenotype and identify Nanog as a central molecular target in this process. Future vaccination technology should consider Nanog an important target to enhance the immunotherapeutic response.

Nanog signaling in cancer promotes stem-like phenotype and immune evasion

“…It is reasonable to posit a model in which Nanog, in conjunction with other factors (which may or may not be present within individual cells), promotes the conversion of tumor cells into CSCs, as has been proposed (8, 26-28). As we and others have shown (14,29,30), besides its ability to turn tumor cells into CSCs, Nanog also confers a growth and survival benefit. Therefore, immune selection favors Nanog + cells, and a fraction of these cells contain the accessory factors necessary to be fully reprogrammed into bona fide CSCs.…”

“…However, the relationship between CSCs and the host immune system is largely unknown. We previously demonstrated in a mouse model that vaccination drives the evolution of tumor cells toward a phenotype resembling CSCs in a process requiring Nanog, a transcription factor pivotal in self-renewal of embryonic stem cells (14). It was unclear at the time whether the emergence of stem-like Nanog + tumor cells was a general consequence of immune selection or merely an artifact of the particular vaccination system we used.…”

“…Transformed cells are continuously subjected to immune selection; cells that can survive immune attack are preferentially retained, while those that cannot are eradicated (3). We have recently shown, in a mouse model of cervical carcinoma, that a vaccination regimen which induces CTL-mediated immune selection drives the evolution of tumor cells toward a stem-like and antiapoptotic phenotype in a process that requires the Nanog transcription factor (14). This finding argues that immune selection can be a perpetuating force for cancer progression.…”

Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

“…Thus an improvement in this strategy is urgently needed. A possible explanation for these limited clinical results may lie in the failure to target CICs, a hypothesis corroborated by the evidence that an increase in "stemness" profile was obtained in postvaccinated glioblastoma patients and following antitumor T cell activity (8,9). We have previously characterized the immune profile of CICs isolated from glioblastoma multiforme (GBM) tissues and found low immunogenicity (10).…”

Preclinical vaccines against mammary carcinoma

“…Those treatments designed to shrink the bulk of a tumor may fail to eliminate the small fraction of cancer stem cells endowed with chemo-and radio-resistance and immune-evasive features [46]. In some cases, the vaccine-induced response against antigens identified in the bulk of the tumor, may even drive the selection of cancer stem cells and promote tumor growth [47]. Instead, for therapy to be more effective, debulking of differentiated tumors must occur followed by targeting of the remaining surviving often quiescent cancer stem cells.…”