Revealing the role of receptor WSX1: a double-edged sword in tumor progession

Tumor initiation and progression are dependent on both aberrant gene expression in tumor cells and the communication between tumor cells and its micro- and systemic microenvironment. Many tumor suppressor genes and oncogenes have been characterized to suppress or promote tumor growth, but fewer genes in tumors are well-characterized as interacting with immune cells in the host to promote or inhibit tumor growth. The interleukin (IL) 27 receptor WSX1 is expressed in immune cells and induces an IL27-dependent immune response. Opposing this conventional dogma, our initial results reveal a much higher level of WSX1 expression in multiple types of epithelial tumor cells when compared to normal epithelial cells. These revelations suggest a role for WSX1 in tumor development, and thus a possible target in cancer immune-therapy. Using genetically modified tumor cells, our studies show that the expression of WSX1 in tumor cells regulates the communication between tumor and host cells resulting in two different consequences. In both the cervical cell line TC1 and the squamous carcinoma cell line AT84, overexpression of WSX1inhibited tumorigenicity both in vivo and in vitro. Sensitizing NK cell-mediated surveillance through upregulation of NKG2D ligands in tumor cells is the underlying mechanism by which WSX1 inhibits tumor growth. Further investigations into other cell lines, such as colon cancer (CT26) and Lewis Lungs Carcinoma (LLC), confirmed the role of WSX1 as a tumor suppressor in vitro. In contrast to the role that WSX1 plays in the aforementioned cells, aggressive LLC and melanoma AGS tumor cells expressing WSX1 grow faster than the control cohorts. These studies reveal that the principal mechanism by which WSX1 promotes tumor growth is the inhibition of T cell proliferation and production of the effector cytokine IFNγ both in the tumor microenvironment and distal lymphatic tissues. Our evidence reveals that this effect is initiated via direct tumor cell and immune cell contact. This important observation reveals a new pathway of tumor-host interaction, which will ultimately lead to better strategies in immune therapy to reverse tumor tolerance

Mutant p53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss in vivo. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death

p53R172H and p53R245W Hotspot Mutations Drive Distinct Transcriptomes in Mouse Mammary Tumors Through a Convergent Transcriptional Mediator

Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/− or MaPR245W/− mammary tumors to MaP−/− tumors revealed (1) differences in cancer-associated pathways activated in both p53 mutants and (2) Nr5a2 as a novel transcriptional mediator of distinct pathways in p53 mutants. Meta-analyses of human breast tumors corroborated these results. In vitro assays demonstrate mutant p53 upregulates specific target genes that are enriched for Nr5a2 response elements in their promoters. Co-immunoprecipitation studies revealed p53R172H and p53R245W interact with Nr5a2. These findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer

WSX1 Expression in Tumors Induces Immune Tolerance via Suppression of Effector Immune Cells

Crosstalk between tumor cells and the cognate microenvironment plays a crucial role in tumor initiation and progression. However, only a few genes are known to affect such a crosstalk. This study reveals that WSX1 plays such a role when highly expressed in tumor cells. The expression of WSX1 in Lewis Lung Carcinoma (LLC) and the melanoma cell line AGS induces the death of T cells and inhibits the production of the effector cytokine IFNγ from NK and T cells, resulting in the promotion of tumor growth. These pro-tumorigenic properties of WSX1 are independent of IL27. This key observation reveals a new pathway of tumor-host interaction, which will ultimately lead to better strategies in immune therapy to reverse tumor tolerance

Deciphering how mutant p53 suppresses innate immune response by Toll-like receptors in a triple-negative breast cancer model

https://openworks.mdanderson.org/sumexp21/1097/thumbnail.jp

Intricacies for Posttranslational Tumor-Targeted Cytokine Gene Therapy

The safest and most effective cytokine therapies require the favorable accumulation of the cytokine in the tumor environment. While direct treatment into the neoplasm is ideal, systemic tumor-targeted therapies will be more feasible. Electroporation-mediated transfection of cytokine plasmid DNA including a tumor-targeting peptide-encoding sequence is one method for obtaining a tumor-targeted cytokine produced by the tumor-bearing patient’s tissues. Here, the impact on efficacy of the location of targeting peptide, choice of targeting peptide, tumor histotype, and cytokine utilization are studied in multiple syngeneic murine tumor models. Within the same tumor model, the location of the targeting peptide could either improve or reduce the antitumor effect of interleukin (IL)12 gene treatments, yet in other tumor models the tumor-targeted IL12 plasmid DNAs were equally effective regardless of the peptide location. Similarly, the same targeting peptide that enhances IL12 therapies in one model fails to improve the effect of either IL15 or PF4 for inhibiting tumor growth in the same model. These interesting and sometimes contrasting results highlight both the efficacy and personalization of tumor-targeted cytokine gene therapies while exposing important aspects of these same therapies which must be considered before progressing into approved treatment options