Into the Microverse of Prostate Cancer from Microenvironment's Immune Modulation to the Complexity of Tumour Heterogeneity

( Dr. Andrea Alimonti from the Institute of Oncology of Southern Switzerland opened this session with a talk entitled “The Role of Innate Tumor Immunity in Prostate Cancer”. “Our team’s main focus is to understand the mechanisms of initiation and progression of CRPC and to evaluate potential therapeutic strategies to revert CRPC again to a hormone-sensitive stage or either to treat the castration resistance condition due to tumor innative response”.

Alimonti et al were the first to generate an in-vitro Prostate Cancer (PCa) PTEN knock-out model in 2010, and since then different in vivo mouse models were generated to better understand CRPC initiation, progression, and metastases’ spreading. Dr. Alimonti presented the results of the research of Di Mitri, Calcinotto, et al published in Nature in 2014, where a subset of cells known as Polymorphonuclear myeloid cells (MDSCs), showed to confer treatment resistance in mice model of PCa treated either with CT or hormonal therapy. Back in 2018 Alimonti, De Bono et al demonstrated the presence of MDSCs infiltration in patient’s metastases with CRPC, and that this subset of cells where enriched compared to HSPC tumor cells (Fig 1)


He then showed the evidence that a high rate of Neutrophil/lymphocyte ratio is associated with resistance to hormonal treatment in PCa. Alimonti continued explaining the possible mechanism of recruiting of MDSCs in the tumor microenvironment. In 2015 he and his team reported the presence of the CXCR2a receptor on MDSCs infiltrating PCa tumor cells and how tumor cells recruited MDSCs by secerning IL-8 analogs like as CCL2. Alimonti displayed then the possible mechanisms through which MDSCs could revert senescence in PCa tumor cells thanks to the production of IL1RA (IL-1 Receptor antagonist). He continued showing how the blockage of the recruiting of MDSCs into tumor cells could “enhance the efficacy of standard therapy such as chemotherapy or androgen deprivation therapy”. Dr. Alimonti continued displaying the work of Calcinotto published in Nature in 2018, in which was showed that androgen deprivation therapy promotes the recruitment of MDSCs into PCa tumor cells (fig 2). He then explained that MDSCs when co-cultured with enzalutamide-sensitive PCa cells could induce resistance to ENZA through the ROR3-γ pathway.


Alimonti continued by showing evidence of Mice models in which an ILR knockout or either ILR antagonization performed better than androgen deprivation therapy. Dr. Alimonti continued displaying the ACE trial results, a phase I/II in the setting of CRPC patients treated with Enzalutamide + AZD5069 a CXCR2a antagonist. “ This was the first trial in the setting of PCa in which a compound that targets not cancer cells but immune cells elicits a positive response in PCa (Partial response (PR) was observed in 2/15 response-evaluable patients and 10/15 patients had stable disease (SD) with duration spanning from <2 months to >16 months)1

Dr. Alimonti closed his talk by showing the possible reasons and mechanisms of resistance to the experimental combination strategy. One possible explanation could be related to other different chemokynes able to recruit MDSCs, he then displayed the significant upregulation of BGN, SPP1, and HGF in PCa cells, which can recruit and promote MDSCs. “All these 3 factors are controlled by MNK, and by blocking AKT, with ipatasertinib together with an MNK inhibitor (eFT508) we were able to revert the phenotype of PCa cells and to impact on the recruiting of MDSCs, reactivating a positive immune response to the tumor” (Fig. 3).


The next speaker was Dr. Del Re who focused her talk on the heterogeneity of PCa and predictive biomarkers of response and resistance. The tumor heterogeneity

“PCa is a heterogeneous disease from a clinical, morphological, and molecular perspective, determined by heritable genetic and epigenetic alteration,” said Dr. Del Re, while showing the literature evidence and morphological examples of tumor heterogeneity not only among different lesions but also mentioning the intratumor heterogeneity. “Underlie morphological heterogeneity there is genetic and molecular heterogeneity, ”said showing subclonal different cells expression of PTEN (Fig. 4).


“The treatment makes a selective pressure on the different subclonal subtypes allowing proliferation and differentiation of resistant cells”. After that Dr. Del Re showed the “strange unlucky story” of AR-V7 which is related to Enzalutamide and Abiraterone resistance. “There is plenty of evidence in the literature of these findings, but still we do not use this biomarker in clinical practice,” said Dr. Del Re, while suggesting that validated cut-off threshold should be helpful to address which tumor could be considered resistant to Hormonal therapy and which could not (Fig 5)


Dr. Del Re showed thereafter a series of other possible mechanisms of resistance to hormonal therapy like the AR overexpression, AR’s punctiform mutations, like F877L mutation which leads to a receptor’s conformation modification, changing the downstream effect of NHA-AR interaction, leading to an agonist effect instead of inhibition.

Dr. Del Re then showed the work of Beltram and Demichelis in which was shown the different gene expression profiles between adenocarcinoma and neuroendocrine CRPC, with a significantly higher rate of nonsynonymous mutation of TP53, FOXA1, and RB1, which could contribute to the more resistant and aggressive phenotype. “If BRAF is a driver gene mutation, why Colorectal cancer does not respond to the same drug as melanoma?” asked Dr. Del Re, “Due to the different gene-dialogue and connection in different tumors. And maybe one day, we’ll understand how genes dialogue, to better treat our patient,” said Dr. Del Re closing his Talk.


Presented by:
  • Andrea Alimonti, MD, Researcher, Oncology, Bellinzona, Switzerland
  • Marzia del Re, MD, Researcher, Pharmacology, Pisa, Italy
Written by: Emanuele Crupi, MD, Resident in Medical Oncology at San Raffaele University Hospital, Milan, @emanuele_crupi on Twitter during the 1st San Raffaele Urologic Oncology Retreat, Friday, Nov 25, 2022

  1. AZD5069 plus Enzalutamide Is Shown to Be Active in MCRPC.