How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer

Abstract Background Advanced prostate cancer remains one of the most common and deadly cancers, despite advances in treatment options. Immunotherapy has provided little benefit to a majority of patients, largely due to the immunosuppressive tumor microenvironment that gives rise to inherently “cold tumors”. In this review, we discuss the immunopathology of the prostate tumor microenvironment, strategies for treating prostate cancer with immunotherapies, and a perspective on potential approaches to enhancing the efficacy of immunotherapies. Methods Databases, including PubMed, Google Scholar, and Cochrane, were searched for articles relevant to the immunology of prostate cancer. We discuss the impact of different types of treatments on the immune system, and potential mechanisms through which prostate cancer evades the immune system. Results The tumor microenvironment associated with prostate cancer is highly immunosuppressive due to (1) the function of regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSCs), (2) the cytokine milieu secreted by tumor stromal cells and fibroblasts, and (3) the production of adenosine via prostatic acid phosphatase. Both adenosine and tumor growth factor beta (TGF-beta) serve as potent immunosuppressive molecules that could also represent potential therapeutic targets. While there have been many immunotherapy trials in prostate cancer, the majority of these trials have targeted a single immunosuppressive mechanism resulting in limited clinical efficacy. Future approaches will require the integration of improved patient selection as well as use of combination therapies to address multiple mechanisms of resistance. Conclusion Prostate cancer inherently gives rise to multiple immunosuppressive mechanisms that have been difficult to overcome with any one immunotherapeutic approach. Enhancing the clinical activity of immunotherapies will require strategic combinations of multiple therapies to address the emerging mechanisms of tumor immune resistance.

Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression

Nutrients ◽

10.3390/nu13124503 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4503

Author(s):

Andreia Matos ◽

Marcos Carvalho ◽

Manuel Bicho ◽

Ricardo Ribeiro

Keyword(s):

Prostate Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Urea Cycle ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Prostate Cancer Progression ◽

Arginine Metabolism ◽

Arginine Deprivation ◽

Arginine availability and activation of arginine-related pathways at cancer sites have profound effects on the tumor microenvironment, far beyond their well-known role in the hepatic urea cycle. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms, either through an arginase-mediated effect on polyamines and proline synthesis, or by the arginine/nitric oxide pathway in tumor cells, antitumor T-cells, myeloid-derived suppressor cells, and macrophages. This review presents evidence concerning the impact of arginine metabolism and arginase activity in the prostate cancer microenvironment, highlighting the recent advances in immunotherapy, which might be relevant for prostate cancer. Even though further research is required, arginine deprivation may represent a novel antimetabolite strategy for the treatment of arginine-dependent prostate cancer.

Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

10.1101/2020.12.07.415299 ◽

2020 ◽

Author(s):

S. Mahnaz ◽

L. Das Roy ◽

M. Bose ◽

C. De ◽

S. Nath ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathways ◽

Suppressor Cells ◽

Ductal Adenocarcinoma ◽

Myeloid Derived Suppressor Cells ◽

Mucin 1 ◽

Transmembrane Glycoprotein ◽

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

Tumor Microenvironment as A “Game Changer” in Cancer Radiotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms20133212 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3212 ◽

Cited By ~ 34

Author(s):

Magdalena Jarosz-Biej ◽

Ryszard Smolarczyk ◽

Tomasz Cichoń ◽

Natalia Kułach

Keyword(s):

Immune System ◽

Tumor Microenvironment ◽

Blood Vessels ◽

Tumor Hypoxia ◽

Suppressor Cells ◽

Anticancer Efficacy ◽

Anti Cancer ◽

Radiation Induced ◽

Game Changer

Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the “in situ” vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.

Crosstalk between myeloid‐derived suppressor cells and the immune system in prostate cancer

Journal of Leukocyte Biology ◽

10.1002/jlb.4ru0819-150rr ◽

2019 ◽

Vol 107 (1) ◽

pp. 43-56 ◽

Cited By ~ 4

Author(s):

Mohammad‐Javad Sanaei ◽

Loghman Salimzadeh ◽

Nader Bagheri

Keyword(s):

Prostate Cancer ◽

Immune System ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells

The impact of Charlson Comorbidity Index on survival outcomes in men with prostate cancer who underwent definitive prostate radiotherapy.

10.1200/jco.2019.37.7_suppl.114 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 114-114

Author(s):

Ahmed I. Ghanem ◽

Remonda M Khalil ◽

Gehan Abd Elatti Khedr ◽

Amy Tang ◽

Amr A. Elsaid ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Charlson Comorbidity Index ◽

Treatment Options ◽

Patient Counselling ◽

Prostate Radiotherapy ◽

Survival Endpoints ◽

Comorbidity Index ◽

114 Background: Life expectancy is very essential in deciding treatment options in men with prostate cancer (PCa); however, the impact of comorbidities on outcomes is not well-established. We investigated the influence of Charlson Comorbidity Index (CCI) on survival endpoints in men with localized PCa who were treated with prostate radiotherapy (RT). Methods: Men with intermediate and high risk PCa who were treated with definitive RT between 1/2007 and 12/2012 were included. Groups were created according to their baseline CCI score at diagnosis into no, mild and severe comorbidity (CCI 0, 1 or 2+). The groups were then compared based on patients’ characteristics and prognostic factors. Kaplan-Meier curves and Uni/multivariate analyses (MVA) were used to examine the impact of CCI groups on overall (OS), disease specific (DSS), and biochemical relapse free (BRFS) survival. Results: 257 patients were identified after excluding low risk, metastatic cases and those with inadequate follow up. Median follow-up was 92 months (range: 2-135) and median age was 73 years (range: 48-85). 53% of the cases were black and 67% were of intermediate risk. Median RT dose was 76 Gy and 47% received androgen deprivation therapy. CCI groups 0, 1 and 2+ encompassed 76 (30%), 54 (21%) and 127 (49%) patients, respectively. Groups were generally well-balanced. 10 and 15 years OS was significantly different across CCI groups (76% & 53%, 46% & 31% and 55% & 14%, for CCI-0, 1 and 2+ respectively; p < 0.001). CCI-0 had better DSS than CCI-2+ ( p = 0.03) with no difference for CCI-0 vs 1 ( p = 0.1). BRFS was non-different among CCI groups ( p = 0.99). On MVA, increased CCI was deterministic for OS ( p < 0.001) after adjusting for age, Gleason’s score and T-stage. For DSS, only age and T3 vs T1/2 were independently prognostic ( p < 0.001); whereas CCI-1 vs 0 was only marginal ( p = 0.05). Conclusions: Higher CCI was a significant predictor of shorter OS in intermediate and high-risk PCa. Baseline comorbidities should be taken into consideration during patient counselling for treatment options and in designing prospective trials for men with localized prostate cancer.

National survey of advanced prostate cancer patients reveals disparity between perceptions and reality of treatment

10.1200/jco.2006.24.18_suppl.8590 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 8590-8590

Author(s):

T. N. Kirk ◽

M. A. Moyad

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Online Survey ◽

Treatment Options ◽

Additional Treatment ◽

Hormone Refractory ◽

Strongly Agree ◽

Additional Education ◽

8590 Background: Over 50,000 men developed hormone refractory prostate cancer (HRPC) in 2005 (CancerMetrics 2005). The objective of this analysis is to understand patient attitudes towards advancing prostate cancer (PC) and treatment. Methods: Patients were recruited from NexCura’s database of users and links from PC websites: UsTOO, PCRI, PCF and PAACT. Board certified physicians who treat HRPC were recruited by J. Reckner & Assoc. Responses were collected via online survey and analyzed by TSC, a division of Yankelovich. Grant funding from Abbott. The scale was “agree”, strongly agree”, “disagree” or “strongly disagree.” Results: 409 HRPC patients (P), 236 caregivers (C), 100 urologists (U) and 104 oncologists (O) participated. 45% of patients have metastatic HRPC. Mean patient age was 65.7 and age at diagnosis was 60.2. Conclusions: Many patients and caregivers have difficulty with advancing PC. Respondents recognize the survival benefit associated with chemotherapy, but attitude on its impact on quality of life varies significantly. Disparity exists between patients, caregivers and physicians on the impact of treatment on quality of life. Additional education, enhanced dialogue and additional treatment options are needed for HRPC patients, caregivers and physicians. [Table: see text] [Table: see text]

A population-based study examining the impact of a multidisciplinary rapid access clinic on utilization of initial treatment options for patients with localized prostate cancer.

10.1200/jco.2013.31.31_suppl.15 ◽

2013 ◽

Vol 31 (31_suppl) ◽

pp. 15-15

Author(s):

Clement K. Ho ◽

Joseph D. Ruether ◽

Bryan J Donnelly ◽

Marc Kerba

Keyword(s):

Prostate Cancer ◽

Initial Treatment ◽

Treatment Options ◽

Population Level ◽

Treatment Decisions ◽

Population Based ◽

Localized Prostate Cancer ◽

Rapid Access ◽

Rapid Access Clinic ◽

15 Background: Treatment decisions in localized prostate cancer (LPCa) are complicated by the variety of available options. A rapid access cancer clinic (RAC) has been unique to Calgary, Alberta (AB) since 2007. RAC offers multidisciplinary prostate cancer care by a urologist, medical oncologist, and radiation oncologist. It is hypothesized that treatment utilization data from decisions taken at RAC may serve to benchmark the appropriateness of treatment decisions on a population level. Objectives: To compare utilization rates for initial treatment of LPCa between AB and RAC. Methods: Records of patients with clinically LPCa in AB between 2007-9 were reviewed with ethics approval. Records were linked to the AB cancer registry database. Clinical, treatment and health services characteristics pertaining to patients attending RAC were compared to those managed elsewhere in AB. The primary endpoints were utilization rates by initial treatment; prostatectomy (P), radiotherapy (RT), hormone therapy (H), active surveillance (A). A logistics regression model was constructed to examine the influence of RAC on initial treatment decisions, while controlling for interactions and factors of interest. Results: 2,660 patients were diagnosed with LPCa. 375 presented to RAC. Utilization rates among RAC patients: P-60.3% (95%CI: 55.3-65.2), A-16%(12.3-19.7), RT-11.7%(8.5-15.0) and H-8.0%(CI:5.2-10.8). This compares to AB rates of P-47.2%(45.9-48.3), A-6.1%(15.2-17.0), RT-18.8%(17.9-19.7), and H-14.5%(13.6-15.4). On multivariate analysis, RAC was associated with a trend towards receiving RT (OR 1.6, p=0.097). Conclusions: A specialized clinic for LPCa may be associated with a higher likelihood of receiving radiotherapy as initial treatment compared to the prostate cancer population in Alberta.

Survey of ADT-induced estrogen deficiency-related side effects in a contemporary cohort of men with advanced prostate cancer.

10.1200/jco.2020.38.6_suppl.235 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 235-235

Author(s):

Robert H. Getzenberg ◽

Mark C. Scholz ◽

Alexandra Scholz ◽

Mitchell S. Steiner

Keyword(s):

Prostate Cancer ◽

Side Effects ◽

Hormonal Therapy ◽

Advanced Prostate Cancer ◽

Treatment Options ◽

Hot Flashes ◽

Estrogen Deficiency ◽

Medical Need ◽

Clinically Significant ◽

235 Background: Androgen Deprivation Therapy (ADT) is a mainstay in the treatment of advanced prostate cancer. ADT-induced estrogen deficiency related side effects may cause men to delay, pause, or discontinue ADT, increases morbidity and mortality, and can significantly impact quality of life. ADT-induced effects include hot flashes, bone loss and fractures, fatigue, decreased libido, and metabolic and lipid changes. Currently there are no FDA approved treatments for ADT-induced hot flashes in men with advanced prostate cancer. In this study, a survey was conducted on the impact of hot flashes, one of the hallmark ADT-induced estrogen deficiency effects, in a contemporary cohort. Methods: During the period of August/September 2019, 212 men with advanced prostate cancer on ADT participated in a digital survey conducted by the Prostate Cancer Research Institute (PCRI) focused on the frequency, severity and impact of their hot flashes. The men were at least 50 years of age with 61% being 70 or older. ADT types included LUPRONÒ(64%), ELIGARDÒ(12%), ZOLADEXÒ(7%) and other forms of hormonal therapy (17%). Results: Of the 212 men surveyed, 99% reported hot flashes with 80% indicating that they experience clinically significant, moderate to severe hot flashes. 77% of men reported that the number of hot flashes stayed the same or increased during their hormonal therapy. 37% of the men experienced more than 5 hot flashes per day and 23% indicated that they felt embarrassed about their hot flashes. Only 51% had either researched how to address their hot flashes or discussed them with their physician. Importantly, 16% considered halting ADT as a result of their hot flashes. Conclusions: This contemporary survey underscores the significant unmet medical need to treat moderate to severe hot flashes which occurred in 80% of the men studied. As about half of the men have not discussed their symptoms with a physician either because of embarrassment or lack of treatment options, the number of men with moderate to severe hot flashes appears to be greatly under-reported. As men on ADT are living longer with prostate cancer, finding an effective and safe treatment for debilitating hot flashes must be a priority.

Patients with undetectable PSA 2 years after docetaxel for metastatic castration sensitive prostate cancer (mCSPC).

10.1200/jco.2021.39.15_suppl.e17044 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e17044-e17044

Author(s):

Mohammad O. Atiq ◽

Shruti Gandhy ◽

Fatima Karzai ◽

Marijo Bilusic ◽

Lisa M. Cordes ◽

...

Keyword(s):

Prostate Cancer ◽

Treatment Options ◽

High Volume ◽

Clinical Activity ◽

Castration Resistant Prostate Cancer ◽

Therapeutic Cancer Vaccine ◽

Volume Group ◽

Low Volume ◽

To Receive

e17044 Background: Patients with mCPSC have multiple treatment options to combine with androgen deprivation therapy (ADT) including docetaxel, abiraterone, enzalutamide and apalutamide, all of which have demonstrated a survival advantage. While oral anti-androgens are administered daily until progression but are less toxic, docetaxel has more upfront side effects. One of the advantages of using docetaxel is that the 6-cycle regimen (over approximately 4 months) potentially affords patients a respite from daily therapies thereafter. Furthermore, docetaxel may be more cost-effective. In this prospective study, mCSPC patients were treated with docetaxel and Prostvac, a therapeutic cancer vaccine. Since this study was initiated, Prostvac did not demonstrate independent clinical activity in a phase 3 trial in metastatic castration resistant prostate cancer. Nonetheless, this study provides an opportunity to evaluate responses to docetaxel-based therapy in mCSPC. Methods: Eligible patients included those with mCSPC and ECOG of ≤ 2. All patients were treated with docetaxel and were planned to receive 75mg/m2 for 6 cycles within 4 months of starting ADT, as per the CHAARTED regimen. Patients were randomized to receive Prostvac prior to, concurrent with or after docetaxel. Patients were restaged annually with CT and Tc99 bone scan. The study was powered to evaluate immunologic responses, which is ongoing. For the purposes of this analysis, all patients were analyzed as one group and long-term PSA responses were evaluated. Results: The study enrolled 73 patients. Age range was 41-86 with a median of 63 years. Race distribution was 71.6% White, 20.3% Black, 4.1% other, and 4.1% unknown. Gleason scores were 6 (4.1%), 7 (21.6%), and 8-10 (68.9%), with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Low-volume disease represented 41.1% of patients and high-volume was 58.9%. After 2 years from the start of ADT, 22% of all patients had PSA values of ≤ 0.2 ng/mL. This included 37% of the low-volume group and 12% of the high-volume group. Three years from the start of ADT, 14% of all patients had PSA values ≤ 0.2 ng/mL (20% of the low-volume group, 9% of the high-volume group). Conclusions: These data highlight long-term outcomes of 6 cycles of docetaxel for men with mCSPC. Although there are concerns about the short-term toxicity of docetaxel, there is potential for prolonged stable disease after ̃4 months of chemotherapy that allows these patients to defer additional oral anti-androgen therapy for years in some patients. The proportions of patients presented here are an underestimate of those who could continue to be monitored for slowly rising, but low PSAs, before starting the next line of therapy. Additional research is required to determine the optimal therapeutic sequence for men diagnosed with mCSPC and long-term implications for quality of life and cost-effectiveness. Clinical trial information: NCT02649855.

Effect of Octreotide Long-Acting Release on Tregs and MDSC Cells in Neuroendocrine Tumour Patients: A Pivotal Prospective Study

Cancers ◽

10.3390/cancers12092422 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2422

Author(s):

Claudia von Arx ◽

Giuseppina Rea ◽

Maria Napolitano ◽

Alessandro Ottaiano ◽

Fabiana Tatangelo ◽

...

Keyword(s):

Immune System ◽

Prospective Study ◽

Neuroendocrine Tumour ◽

Hormone Secretion ◽

Somatostatin Receptors ◽

Growth Hormone Secretion ◽

Suppressor Cells ◽

Neuroendocrine Neoplasms ◽

Long Acting ◽

Octreotide long-acting repeatable (LAR) is largely used to treat functional and/or metastatic neuroendocrine neoplasms (NENs). Its effect in controlling carcinoid syndrome and partially reduce tumour burden is attributable to the ability of octreotide to bind somatostatin receptors (SSTRs) on the tumour and metastasis, regulating growth hormone secretion and cell growth. Notably, SSTRs are also expressed, at different levels, on Tregs. Tregs, together with myeloid-derived suppressor cells (MDSCs), are key components in the anti-tumour immunoregulation. This is the first prospective study aimed to explore the impact of Octreotide (OCT) LAR on the immune system, with a particular focus on Tregs and MDSC cells. Here, we show that circulating Tregs are elevated in NENs patients compared to healthy donors and that treatment with OCT LAR significantly decrease the level of total Tregs and of the three functional Tregs populations: nTregs, eTregs and non-Tregs. Furthermore, OCT LAR treatment induces a functional impairment of the remaining circulating Tregs, significantly decreasing the expression of PD1, CTLA4 and ENTPD1. A trend in circulating MDSC cells is reported in patients treated with OCT LAR. The results reported here suggest that the effect of OCT LAR on Tregs could tip the balance of the patients’ immune-system towards a durable anti-tumour immunosurveillance with consequent long-term control of the NENs disease.