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Immune checkpoint inhibitors (ICIs) use antibodies that block cell surface immune checkpoint proteins with great efficacy in treating immunogenic or “immune hot” tumors such as melanoma, kidney, and lung adenocarcinoma. ICIs have limited response rates to other non-immunogenic cancers. The tumor microenvironment (TME) consists of many cell types that collectively promote tumor progression. Cancer therapeutics are commonly designed to target one molecule in one defined cell type. There is growing evidence that long-term therapeutic responses require the targeting of cancer cells and tumor-promoting populations within the TME. The question remains whether we can identify targetable molecules/pathways that are critical for multiple cell types. Here, we will discuss several molecular targets that may fit a “two or multiple birds, one stone” model, including the B-cell lymphoma-2 (BCL-2) family pro-survival factors, transcriptional factors including signal transducer and activator of transcription 3 (STAT3), the nuclear receptor 4A family (NR4A1, NR4A2, NR4A3), as well as epigenetic regulators such as bromodomain and extra-terminal (BET) family proteins, histone deacetylase (HDAC) family, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) and lysine-specific demethylase 1 (LSD1/KDM1A). We will focus on the rationale of these targets in immune modulation, as well as the strategies for targeting these important proteins for cancer therapy.

Supplementary Table S1. Index of genes upregulated or downregulated in basal-TIC tumors relative to luminal-TIC tumors. Supplementary Table S2. WNT5A CNV by PAM50 molecular subtype from samples with both RNAseq expression data and CNV (n=807). Figure S1: Verification of Illumina Array by reverse transcription real-time PCR analysis (Supplementary for Figure 1). Figure S2: Allelic loss of WNT5A led to decreased WNT5A expression in human breast-cancer specimens and mouse luminal epithelial cells. Figure S3: Schematic depiction of the purification procedure for different populations of mammary epithelial cells. Figure S4: Supplementary information of Figure 4. Figure S5: Heterozygous deletion of Wnt5a has no impact on normal mammary gland development. Figure S6: WNT5A induces the phosphorylation of SMAD2. Figure S7: Differential expression of canonical and noncanonical Wnt receptors in basal and luminal epithelial cells. Figure S8: RYK or SMAD2 expression does not correlate with metastasis-free survival. Figure S9: Schematic depiction of the major conclusions and explained in detail in the Discussion section.

It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared with the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFβ substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFβR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of the TGFβ–SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal–luminal cross-talk in normal mammary tissue. Cancer Res; 75(10); 1972–82. ©2015 AACR.

Renal cell carcinoma (RCC) is the 7th most common type of cancer, with over 400,000 new cases each year and 170,000 deaths worldwide. RCCs are grouped into several histological subtypes, with clear cell renal cell carcinoma (ccRCC) being the most common and most aggressive type. The first line of therapy for ccRCC is tyrosine kinase inhibitors (TKIs) which target multiple kinases including the VEGF receptor. The treatment can be used alone or in combination with immune checkpoint inhibitors. However, most patients develop resistance to the TKIs within six months of treatment. Therefore, our aim is to develop novel single or combinatorial therapies and discover ways to overcome the resistance to TKIs. By analyzing TCGA and published datasets from GEO, we found that angiopoietin-like 4 (ANGPTL4) is significantly elevated in both the WT and TKI-resistant ccRCC tumors. ANGPTL4 has been shown to participate in angiogenesis in several other tumor models, and blocking ANGPTL4 with an antibody in vitro, reduces the angiogenic potential of 786-O and RCC4 human ccRCC cell lines, suggesting a pro-angiogenic effect of ANGPTL4 in ccRCC. Knockout of ANGPTL4 in Caki-1 xenograft tumor model significantly reduced tumor angiogenesis and increased vessel normalization, as evidenced by increased expression of VEGFR2 and adhesion molecules on endothelial cells. The increased normalization of blood vessels is an indication of the therapeutic potential of combing anti-ANGPTL4 therapy with immune checkpoint inhibitors. Furthermore, both knockout of ANGPTL4 in 786-O cells and treatment of 786-O tumor-bearing mice with an ANGPTL4 blocking antibody significantly reduced tumor growth. To illustrate the mechanism of ANGPTL4-induced angiogenesis, we performed live cell receptor capturing to find cANGPTL4 binding partners on the cell membrane of human endothelial cells. After the mass spectrometry analysis, several novel receptors were found, and the top candidate is endothelial cell surface chemotaxis receptor (ECSCR), which is highly expressed on endothelial and adipocytes. Previous studies have shown that ECSCR can potentiate angiogenic signaling, which is similar to our data showing that ANGPTL4 can synergistically increase FGF2-induced angiogenesis. Thus, ANGPTL4 may promote angiogenesis in ccRCC by potentiating other angiogenic signaling via interaction with ECSCR. To summarize, we demonstrated the pro-angiogenic potential of ANGPTL4 in ccRCC and its critical role in tumor development. Knockout or antibody-mediated inhibition of ANGPTL4 reduced tumor angiogenesis and growth and increased vessel normalization. This data supports the therapeutic potential of ANGPTL4 targeted treatment in ccRCC. Citation Format: Zeng Jin, Umasankar De, Lei Wang, Jeremy Kleberg, Weizhou Zhang, Ryan Kolb. Angiopoietin-like 4 as a potential therapeutic target for clear cell renal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 571.

In the original publication [...]

Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.

Simple Summary Clear cell renal cell carcinomas (ccRCC) have several distinct immunological features, including a high degree of immune infiltration and relatively low mutational burdens, the resistance to cytotoxic chemotherapy, and relative sensitivity to anti-angiogenic therapy and immunotherapies. Immune checkpoint inhibitor (ICI) therapy has become standard care in the treatment of ccRCC, but a better understanding of the molecular and cellular characteristics of ccRCC is needed to truly optimize the use of ICI therapy. With a focus on cancer immunology, we summarize the clinical trials of ICIs in ccRCC, the molecular and cellular correlates of these clinical trials, and the single-cell RNA sequencing studies to provide a comprehensive overview of the immune landscape within the ccRCC tumor microenvironment, in particular in the context of ICI therapy. We will discuss potential molecular and cellular biomarkers that can be used to predict therapeutic responses in ccRCC patients. Abstract Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.