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High levels of IL1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL1β blockade induced by the mAbs canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti-programmed cell death protein 1 (anti-PD-1), anti-VEGFα, and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin. Canakinumab and gevokizumab did not show notable efficacy as single-agent therapies; however, IL1β blockade enhanced the effectiveness of docetaxel and anti-PD-1. Accompanying these effects, blockade of IL1β alone or in combination induced significant remodeling of the tumor microenvironment (TME), with decreased numbers of immune suppressive cells and increased tumor infiltration by dendritic cells (DC) and effector T cells. Further investigation revealed that cancer-associated fibroblasts (CAF) were the cell type most affected by treatment with canakinumab or gevokizumab in terms of change in gene expression. IL1β inhibition drove phenotypic changes in CAF populations, particularly those with the ability to influence immune cell recruitment. These results suggest that the observed remodeling of the TME following IL1β blockade may stem from changes in CAF populations. Overall, the results presented here support the potential use of IL1β inhibition in cancer treatment. Further exploration in ongoing clinical studies will help identify the best combination partners for different cancer types, cancer stages, and lines of treatment., (©2023 American Association for Cancer Research.)

Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in the composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells. Here, mouse and human breast tumors were used to examine stromal cells expressing fibroblast activation protein (FAP), a surface marker for CAFs. Two discrete populations of FAP + mesenchymal cells were identified on the basis of podoplanin (PDPN) expression: a FAP + PDPN + population of CAFs and a FAP + PDPN - population of cancer-associated pericytes (CAPs). Although both subsets expressed extracellular matrix molecules, the CAF transcriptome was enriched in genes associated with TGFβ signaling and fibrosis compared with CAPs. In addition, CAFs were enriched at the outer edge of the tumor, in close contact with T cells, whereas CAPs were localized around vessels. Finally, FAP + PDPN + CAFs suppressed the proliferation of T cells in a nitric oxide-dependent manner, whereas FAP + PDPN - pericytes were not immunosuppressive. Collectively, these findings demonstrate that breast tumors contain multiple populations of FAP-expressing stromal cells of dichotomous function, phenotype, and location., (©2018 American Association for Cancer Research.)

A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.

Myeloid cells play important regulatory roles within the tumor environment by directly promoting tumor progression and modulating the function of tumor-infiltrating lymphocytes, and as such, they represent a potential therapeutic target for the treatment of cancer. Although distinct subsets of tumor-associated myeloid cells have been identified, a broader analysis of the complete myeloid cell landscape within individual tumors and also across different tumor types has been lacking. By establishing the developmental and transcriptomic signatures of infiltrating myeloid cells from multiple primary tumors, we found that tumor-associated macrophages (TAM) and tumor-associated neutrophils (TAN), while present within all tumors analyzed, exhibited strikingly different frequencies, gene expression profiles, and functions across cancer types. We also evaluated the impact of anatomic location and circulating factors on the myeloid cell composition of tumors. The makeup of the myeloid compartment was determined by the tumor microenvironment rather than the anatomic location of tumor development or tumor-derived circulating factors. Protumorigenic and hypoxia-associated genes were enriched in TAMs and TANs compared with splenic myeloid-derived suppressor cells. Although all TANs had an altered expression pattern of secretory effector molecules, in each tumor type they exhibited a unique cytokine, chemokine, and associated receptor expression profile. One such molecule, haptoglobin, was uniquely expressed by 4T1 TANs and identified as a possible diagnostic biomarker for tumors characterized by the accumulation of myeloid cells. Thus, we have identified considerable cancer-specific diversity in the lineage, gene expression, and function of tumor-infiltrating myeloid cells., (©2014 American Association for Cancer Research.)

Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments.