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Author(s): Arianna Calcinotto [sup.1] , Clarissa Spataro [sup.1] , Elena Zagato [sup.1] , Diletta Di Mitri [sup.1] , Veronica Gil [sup.2] , Mateus Crespo [sup.2] , Gaston De Bernardis [sup.1] [...], Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.IL-23 produced by myeloid-derived suppressor cells regulates castration resistance in prostate cancer by sustaining androgen receptor signalling.

Cellular senescence is a stable state of cell growth arrest that opposes tumour initiation and progression in a variety of in vivo tumour models (1,2). Recent studies have revealed an [...], Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence (1-3). This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence (4-6). Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice (2,7) are massively infiltrated by a population of [CD11b.sup.+]Gr-[1.sup.+] myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-[1.sup.+] cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Illra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating [CD11b.sup.+] Gr-[1.sup.+] myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2) (8). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.

Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b+Gr-1+ myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1+ cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b+Gr-1+ myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy. [ABSTRACT FROM AUTHOR]

The article presents a study which explores the dual role of endolysosomal two-pore channel two (TPC2) in malignant traits of melanoma cells. It mentions that how the genetic or pharmacological inhibition of TPC2 impacts on either malignant phenotype. It discusses that inhibition of TPC2 determines anti-oncogenic responses.

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies. [ABSTRACT FROM AUTHOR]

The ion channel TPC2, localized on the membranes of acidic organelles such as endo-lysosomes and melanosomes, is known to play a role in relevant pathologies, e.g. tumor metastasis and viral infection. We set out to explore a so far neglected aspect of its functions, i.e. the impact of TPC2 in the cross-talk between tumor cells and tumor microenvironment, an interaction known to regulate tumor aggressiveness. Data showing that TPC2 participatesin the regulation of autophagy and secretionsuggest focusing on these functions and their interrelations. Relevant is the known plasticity of macrophages that, in response to tumor microenvironmental cues undergo a phenotypic switch (polarization) from anti-tumoral (M1-like) to pro-tumoral (M2-like). Our experimental model is represented by malignant melanoma, a highly insidious malignancy in which we have previously characterized the relevance of TPC2-regulated signaling. In particular, using different melanoma cell lines, human peripheral blood mononuclear cells (hPBMCs) and murine bone marrow precursor cells (BMPs), we tested how TPC2 genetic deletion or pharmacological inhibition can modify the secretoma of either cell type, in turn subverting malignancy traits, among which melanoma radioresistance. Aiming to disclose a novel targetable component in the chain of local interactions regulating the aggressiveness of melanoma, our data show that in mouse and human melanoma cells, TPC2-KO and TPC2 pharmacological inhibition impacts on the autophagic process, radiosensitivity and secretoma, in turn affecting macrophage polarization. [ABSTRACT FROM AUTHOR]