Search

In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetal-antigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal-antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a regulatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetal-maternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francesco Maria Venanzi: no conflict of interest to this manuscript. Marta Bini no conflict of interest to this manuscript. Antonio Nuccio no conflict of interest to this manuscript. Alessandro De Toma: no conflict of interest to this manuscript. Matteo Lambertini: advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo and Takeda, Travel Grants from Gilead and research support (to the Institution) from Gilead outside the submitted work. Francesca Rita Ogliari: no conflict of interest to this manuscript. Sara Oresti: no conflict of interest to this manuscript. Maria Grazia Viganò: no conflict of interest to this manuscript. Elena Brioschi: no conflict of interest to this manuscript. Maggie Polignano: no conflict of interest to this manuscript. Matteo Maria Naldini: no conflict of interest to this manuscript. Silvia Riva: no conflict of interest to this manuscript. Michele Ferrara: no conflict of interest to this manuscript. Nicola Fogale: no conflict of interest to this manuscript. Giuseppe Damiano: no conflict of interest to this manuscript. Vincenzo Russo: no conflict of interest to this manuscript. Michele Reni: no conflict of interest to this manuscript. Giulia Veronesi: no conflict of interest to this manuscript. Giorgia Foggetti: no conflict of interest to this manuscript. Fabio Conforti: no conflict of interest to this manuscript. Alessandra Bulotta: no conflict of interest to this manuscript. Roberto Ferrara: advisory board MSD and Beigene., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

TP63 is a member of the TP53 gene family, sharing a common gene structure that produces two groups of mRNAs' encoding proteins with different N-terminal regions (ΔN and TA isoforms); both transcripts are also subjected to alternative splicing mechanisms at C-terminus, generating a variety of isoforms. p63 is a master regulator of epidermal development and homoeostasis as well as an important player in tumorigenesis and cancer progression with both oncogenic and tumour suppressive roles. A number of studies have aimed at the identification of p63 target genes, allowing the dissection of the molecular pathways orchestrated by the different isoforms. In the present study we investigated in more detail the p63 responsiveness of the WDFY2 (WD repeat and FYVE domain containing 2) gene, encoding for an endosomal protein identified as a binding partner of the PI-3K/AKT signalling pathway. We showed that overexpression of different p63 isoforms was able to induce WDFY2 expression in TP53-null cells. The p63-dependent transcriptional activation was associated with specific response elements (REs) that have been identified by a bioinformatics tool and validated by yeast- and mammal-based assays. Interestingly, to confirm that WDFY2 belongs to the p63 network of cancer regulation, we analysed the impact of WDFY2 alterations, by showing its frequent deletion in different types of tumours and suggesting its expression level as a prognostic biomarker. Lastly, we identified a chromosomal translocation involving the WDFY2 locus in a patient affected by a rare congenital limb anomaly, indicating WDFY2 as a possible susceptibility gene placed downstream p63 in the network of limb development., (© 2019 The Author(s).)

PRIMA-1 is a chemical compound identified as a growth suppressor of tumor cells expressing mutant p53. We previously found that in the MDA-MB-231 cell line expressing high level of the mutant p53-R280K protein, PRIMA-1 induced p53 ubiquitination and degradation associated to cell death. In this study, we investigated the ability of PRIMA-1 to induce autophagy in cancer cells. In MDA-MB-231 and HCT116 cells, expressing mutant or wild type p53, respectively, autophagy occurred following exposure to PRIMA-1, as shown by acridine orange staining, anti-LC3 immunofluorescence and immunoblots, as well as by electron microscopy. Autophagy was triggered also in the derivative cell lines knocked-down for p53, although to a different extent than in the parental cells expressing mutant or wild type p53. In particular, while wild type p53 limited PRIMA-1 induced autophagy, mutant p53 conversely promoted autophagy, thus sustaining cell viability following PRIMA-1 treatment. Therefore, the autophagic potential of PRIMA-1, besides being cell context dependent, could be modulated in a different way by the presence of wild type or mutant p53. Furthermore, since both cell lines lacking p53 were more sensitive to the cytotoxic effect of PRIMA-1 than the parental ones, our findings suggest that a deregulated autophagy may favor cell death induced by this drug., (Copyright © 2013 Elsevier B.V. All rights reserved.)