Downregulating testosterone levels enhance immunotherapy efficiency

Wang, Luoyang; Jiang, Guoqiang; Jing, Nan; Liu, Xuerun; Zhuang, Huiren; Zeng, Wenfeng; Liang, Wei; Liu, Zheng

doi:10.1080/2162402x.2021.1981570

Cited by 10 publications

(14 citation statements)

References 48 publications

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“…40 Smoking has also been shown to increase testosterone levels, which appear to promote melanoma metastasis and contribute to immunotherapy resistance. [41][42][43] The association of persistent smoking vs smoking cessation was not specifically addressed in this study. However, the absence of an overall negative survival association with former smoking in multivariable analysis supports the hypothesis that any negative effect from smoking could be largely reversible.…”

Section: Discussionmentioning

confidence: 99%

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Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Jackson,

Jones,

Fluke

et al. 2024

JAMA Netw Open

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ImportanceWhile smoking is associated with a decreased incidence of cutaneous melanoma, the association of smoking with melanoma progression and death is not well defined.ObjectiveTo determine the association of smoking with survival in patients with early-stage primary cutaneous melanoma.Design, Setting, and ParticipantsThis cohort study performed a post hoc analysis of data derived from the randomized, multinational first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Participants were accrued for MSLT-I from January 20, 1994, to March 29, 2002; MSLT-II, from December 21, 2004, to March 31, 2014. Median follow-up was 110.0 (IQR, 53.4-120.0) months for MSLT-I and 67.6 (IQR, 25.8-110.2) months for MSLT-II. Patients aged 18 to 75 years with clinical stages I or II melanoma with a Breslow thickness of 1.00 mm or greater or Clark level IV to V and available standard prognostic and smoking data were included. Analyses were performed from October 4, 2022, to March 31, 2023.ExposureCurrent, former, and never smoking.Main Outcomes and MeasuresMelanoma-specific survival of patients with current, former, and never smoking status was assessed for the entire cohort and for nodal observation and among subgroups with sentinel lymph node biopsy (SLNB)–negative and SLNB-positive findings.ResultsOf 6279 included patients, 3635 (57.9%) were men, and mean (SD) age was 52.7 (13.4) years. The most common tumor location was an extremity (2743 [43.7%]), and mean (SD) Breslow thickness was 2.44 (2.06) mm. Smoking status included 1077 (17.2%) current, 1694 (27.0%) former, and 3508 (55.9%) never. Median follow-up was 78.4 (IQR, 30.5-119.6) months. Current smoking was associated with male sex, younger age, trunk site, thicker tumors, tumor ulceration, and SLNB positivity. Current smoking was associated with a greater risk of melanoma-associated death by multivariable analysis for the entire study (hazard ratio [HR], 1.48 [95% CI, 1.26-1.75]; P &lt; .001). Former smoking was not. The increased risk of melanoma-specific mortality associated with current smoking was greatest for patients with SLNB-negative melanoma (HR, 1.85 [95% CI, 1.35-2.52]; P &lt; .001), but also present for patients with SLNB-positive melanoma (HR, 1.29 [95% CI, 1.04-1.59]; P = .02) and nodal observation (HR, 1.68 [95% CI, 1.09-2.61]; P = .02). Smoking at least 20 cigarettes/d doubled the risk of death due to melanoma for patients with SLNB-negative disease (HR, 2.06 [95% CI, 1.36-3.13]; P &lt; .001).Conclusions and RelevanceThe findings of this cohort study suggest that patients with clinical stage I and II melanoma who smoked had a significantly increased risk of death due to melanoma. Smoking status should be assessed at time of melanoma diagnosis and may be considered a risk factor for disease progression.

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Section: Discussionmentioning

confidence: 99%

“…Smoking derivative products in individuals is known to alter various immune responses, which may reduce host immune responses in controlling melanoma disease progression . Smoking has also been shown to increase testosterone levels, which appear to promote melanoma metastasis and contribute to immunotherapy resistance …”

Section: Discussionmentioning

confidence: 99%

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Jackson,

Jones,

Fluke

et al. 2024

JAMA Netw Open

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“…The effects of gut microbes on the efficiency of immunotherapy with anti-PD-1/PD-L1 have been extensively reported [ 49 – 52 ]. Our previous study showed that the response efficiency of α PD-L1 was reinforced by colistin in male mice, whereas a detrimental effect of colistin was observed in female mice [ 25 ]. Clinical studies have also indicated that sex-related differences affect the response efficiency to ICIs.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Quarni et al reported that the combined use of anti-PD-L1 mAb ( α PD-L1) with Mit-A, a polyketide antibiotic capable of inhibiting the binding of the transcription factor SP1 to the minor groove of DNA [ 23 ], decreased tumor growth in MC38 tumor-bearing mice [ 24 ]. Our previous study showed that a narrow-spectrum antibiotic, colistin, strengthened the immunotherapy efficiency of anti-PD-L1 in male mice but not in female mice [ 25 ]. Given all these findings, we came to the present study aimed to probe the interplay of antibiotics, gut microbiota, and colitis in the context of ICI therapy, which we believe may shed light on the understanding of the above-mentioned complicated responses and, moreover, the application of immunotherapy with ICIs.…”

Section: Introductionmentioning

confidence: 99%

Sex-Biased Immune Responses to Antibiotics during Anti-PD-L1 Treatment in Mice with Colon Cancer

Jing

Wang

Zhuang

et al. 2022

Journal of Immunology Research

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Colitis is a frequently occurred side effect of immune checkpoint inhibitors (ICIs), which are increasingly used in cancer treatment, whereas antibiotics are widely used to treat colitis, their effectiveness in ICI-associated colitis remains controversial. In this study, we firstly assessed the effectiveness of several commonly used antibiotics and antibiotic cocktails in alleviating of dextran sulfate sodium- (DSS-) induced colitis. We observed that two narrow-spectrum antibiotics, neomycin and metronidazole, were more effective in alleviating colitis, as evidenced by the remission of loss of the body weight, enlargement of the spleen, shortening of the colon, secretion of proinflammatory cytokines, and histological score of the colon tissue. Moreover, these two antibiotics resulted in better relief of colitis symptoms in the MC38 tumor-bearing male mice receiving the anti-PD-L1 mAb (αPD-L1) treatment, compared to the females. In the meantime, an enhanced response to αPD-L1 efficiency against mice colon cancer was observed in the male mouse group upon the application of these two antibiotics. In contrast, both neomycin and metronidazole showed destructive effects on the antitumor efficiency of αPD-L1 in female mice, despite relief from colitis. We found that antibiotic treatment attenuated the increased infiltration of granulocytes and myeloid cells in colon tissue induced by DSS in female mice, while reducing the proportion of Th17 cells in male mice. These differences were further associated with the sex-biased differences in the gut microbiota. These findings indicated that sex-dependent alterations in the gut microbiota should be considered when applying antibiotics for the treatment of ICI-associated colitis.

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“…Initiation of anti-TNF-α therapy in Crohn’s disease results in a rapid and significant increase in gonadotropin levels and sex hormones, together with a reduction in inflammation [ 91 ]. In oncology, it has been demonstrated that reducing testosterone levels can improve the efficacy of immunotherapy [ 92 ]. In allergology, there are several biologic drugs currently authorized, but very little is known about potential gender differences in their efficacy and safety [ 93 , 94 ].…”

Section: Sex and Biological Therapymentioning

confidence: 99%

Sex, Allergic Diseases and Omalizumab

et al. 2022

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Gender differences are increasingly emerging in every area of medicine including drug therapy; however, specific gender-targeted studies are infrequent. Sex is a fundamental variable, which cannot be neglected. When optimizing therapies, gender pharmacology must always be considered in order to improve the effectiveness and safety of the use of drugs. Knowledge of gender differences promotes appropriate use of therapies and greater health protection for both genders. Further development of gender research would make it possible to report on differences in the assimilation and response of the female organism as compared to the male, in order to identify potential risks and benefits that can be found between genders. Furthermore, a better understanding of sex/gender-related influences, with regard to pharmacological activity, would allow the development of personalized “tailor-made” medicines. Here, we summarize the state of knowledge on the role of sex in several allergic diseases and their treatment with omalizumab, the first biologic drug authorized for use in the field of allergology.

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Downregulating testosterone levels enhance immunotherapy efficiency

Cited by 10 publications

References 48 publications

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Sex-Biased Immune Responses to Antibiotics during Anti-PD-L1 Treatment in Mice with Colon Cancer

Sex, Allergic Diseases and Omalizumab

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