Sexual Dimorphism of Immune Responses: A New Perspective in Cancer Immunotherapy

Capone, Imerio; Marchetti, Paolo; Ascierto, Paolo A.; Malorni, Walter; Gabriele, Lucia

doi:10.3389/fimmu.2018.00552

Cited by 83 publications

(56 citation statements)

References 99 publications

(110 reference statements)

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“…In addition, our larger sample size may have allowed for identification of the described sex differences in irAEs. Over the past 3 decades, many studies have suggested differences between sexes in immune responses; this has been observed in vaccination, microbiology, and tumor‐specific studies . Women mount more vigorous antibody‐ and cell‐mediated immune responses than men following either infection or vaccination .…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

et al. 2019

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Background Immune‐related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti‐programmed cell death protein 1 (PD‐1) therapy. Materials and Methods All patients with metastatic melanoma and non‐small cell lung cancer (NSCLC) treated with anti‐PD‐1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan‐Meier method and log‐rank test was used for time‐to‐event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression‐free‐survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune‐related adverse events (irAEs) compared with men when treated with anti‐programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow‐up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment‐related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

et al. 2019

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“…Immunotherapies rely on effective antitumor immunity in the tumor microenvironment, which can be achieved by recruiting tumor-infiltrating leukocytes to the site [315]. As leukocyte populations are dramatically affected by sex, antitumor immune responses may display sexual dimorphisms that impact on the efficacy of cancer immunotherapies [319].…”

Section: Implications For Immunotherapymentioning

confidence: 99%

Sex differences in cancer mechanisms

et al. 2020

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We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab-and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

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“…Overall, our meta-analysis differs from The emerged evidence for the lack of efficacy of anti-CTLA-4 in women invites critical interpretation. The renowned gender-related differences in immune response [13] and the different mechanisms of action of anti-CTLA-4 and anti-PD-1/ PDL-1 [49,50] may help provide a biologic rationale to this finding.…”

Section: Discussionmentioning

confidence: 99%

Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

Grassadonia¹,

Sperduti²,

Vici³

et al. 2018

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Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p<0.001 and HR 0.77, p<0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p<0.012), with the exception of melanoma (in women, HR 0.80, p=0.006). PFS was longer in men than in women (HR 0.67, p<0.001 and HR 0.77, p=0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.

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Sexual Dimorphism of Immune Responses: A New Perspective in Cancer Immunotherapy

Cited by 83 publications

References 99 publications

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

Sex differences in cancer mechanisms

Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

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