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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.

Natural killer cells (NK) are innate lymphocytes endowed with the ability to recognize and kill cancer cells. Consequently, adoptive transfer of autologous or allogeneic NK cells represents a novel opportunity in cancer treatment that is currently under clinical investigation. However, cancer renders NK cells dysfunctional, thus restraining the efficacy of cell therapies. Importantly, extensive effort has been employed to investigate the mechanisms that restrain NK cell anti-tumor function, and the results have offered forthcoming solutions to improve the efficiency of NK cell-based therapies. The present review will introduce the origin and features of NK cells, summarize the mechanisms of action and causes of dysfunction of NK cells in cancer, and frame NK cells in the tumoral microenvironment and in the context of immunotherapies. Finally, we will discuss therapeutic potential and current limitations of NK cell adoptive transfer in tumors. [ABSTRACT FROM AUTHOR]

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]

The present study supports a model in whichPtenloss-induced senescence is hindered in prostate tumor cells by non cell-autonomous mechanisms. Indeed, paracrine signaling by tumor-infiltrating CD11b+Gr-1+myeloid cells triggers senescence evasion in prostate lesions ofPten-null mice, eventually promoting tumor progression. [ABSTRACT FROM AUTHOR]

The article deals with the role of JAK2/STAT3 pathway activation in differentiating the senescence-associated secretory phenotype (SASP) of Pten loss induced-cellular senescence (PICS) and oncogene-induced senescene (OIS). Topics discussed the effect of Pten null prostate conditional mice in developing prostatic intraepithelial neoplasia (PIN), the upregulaton of chemoattractant cytokines and the presence of myeloid derived suppressor cells (MDSC) in the tumor microenvironment.

In the prostate bone metastasis microenvironment, macrophages activate a cascade that involves Activin A, the extracellular matrix, and SRC kinase and drives resistance to anti-androgen therapy. These findings (Li et al., 2023. J. Exp. Med.https://doi.org/10.1084/jem.20221007) have broad implications, including metastasis diversity in different tissue milieus and the interplay between hormones and immunity., (© 2023 Di Mitri et al.)

Macrophages are main players of the innate immune system. They show great heterogeneity and play diverse functions that include support to development, sustenance of tissue homeostasis and defense against infections. Dysfunctional macrophages have been described in multiple pathologies including cancer. Indeed tumor-associated macrophages (TAMs) are abundant in most tumors and sustain cancer growth, promote invasion and mediate immune evasion. Importantly, lipid metabolism influences macrophage activation and lipid accumulation confers pathogenic features on macrophages. Notably, a subset of lipid-loaded macrophages has been recently identified in many tumor types. Lipid-loaded TAMs support tumor growth and progression and exert immune-suppressive activities. In this review, we describe the role of lipid metabolism in macrophage activation in physiology and pathology and we discuss the impact of lipid accumulation in macrophages in the context of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tumor-associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa). The mechanistic basis of this correlation and therapeutic strategies to target TAMs in PCa remain poorly defined. Here, single-cell RNA sequencing was used to profile the transcriptional landscape of TAMs in human PCa, leading to identification of a subset of macrophages characterized by dysregulation in transcriptional pathways associated with lipid metabolism. This subset of TAMs correlates positively with PCa progression and shorter disease-free survival and is characterized by an accumulation of lipids that is dependent on Marco. Mechanistically, cancer cell-derived IL-1β enhances Marco expression on macrophages, and reciprocally, cancer cell migration is promoted by CCL6 released by lipid-loaded TAMs. Moreover, administration of a high-fat diet to tumor-bearing mice raises the abundance of lipid-loaded TAMs. Finally, targeting lipid accumulation by Marco blockade hinders tumor growth and invasiveness and improves the efficacy of chemotherapy in models of PCa, pointing to combinatorial strategies that may influence patient outcomes., Competing Interests: Disclosures: R.A. DePinho reported being a Founder and Advisor for Tvardi Therapeutics, Asylia Therapeutics, Nirogy Therapeutics, Stellanova Therapeutics, and Sporos Bioventures. The focus of these companies is not directly related to the content of this manuscript. S. Gordon reported personal fees from Verseau, Myeloid Therapeutics, and Alnylam outside the submitted work. No other disclosures were reported., (© 2021 Masetti et al.)

Tumor-infiltrating myeloid-derived suppressor cells (MDSC) are a heterogeneous and immunosuppressive cell subset that blocks the proliferation and the activity of both T and natural killer (NK) cells and promotes tumor vasculogenesis and progression. Recent evidences demonstrate that the recruitment of MDSCs in tumors also blocks senescence induced by chemotherapy promoting chemoresistance. Hence, the need of novel therapeutic approaches that can efficiently target MDSC recruitment and function in cancer. Among them, novel combinatorial treatments of chemotherapy and immunotherapy or treatments that induce depletion of MDSCs in peripheral sites should be taken in consideration., (©2015 American Association for Cancer Research.)

Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4(+) effector memory (EM) T cells (CD27(-)CD45RA(-)) and also EM T cells that re-express CD45RA (CD27(-)CD45RA(+); EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear γH2AX after TCR activation. A paradoxical observation was that although CD4(+) EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27(+)CD45RA(-)) and EM (CD27(-)CD45RA(-)) CD4(+) T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-α inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4(+) EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4(+) T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4(+) EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4(+) T cells. In particular, CD4(+) EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible.

FoxP3⁺ Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS), an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis.