Introduction
Immune checkpoint inhibitor (ICI) has become one of the most important cancer therapy (1). However, various factors might affect the therapeutic effect of ICI, including tumor micro-environment, systemic immune status, etc. It is believed that the innate and adaptive immune responses of women are higher than those of men. Women could eliminate pathogens faster than men (2); furthermore, about 80% of patients with autoimmune diseases are women (3). This difference in the immune system might affect the natural course of cancer as the mortality caused by various cancers in men is nearly twice than that of women (4). This phenomenon might not only be related to differences in behavioral factors, but also be related to the difference in the immune system between sexes. Animal studies have already shown that sex hormones could regulate the expression and function of PD-1 and PD-L1 (5). Also, the efficacy of anti-PD-L1 mAb was higher in male than that of female mice in the mouse melanoma model (6). As a result, understanding the impact of sex on immune checkpoint inhibitor therapy becomes particularly critical because it might change the strategy for cancer patients of different sexes. Meta analysis could solve unsettled clinical problems. In this article, we explored some of the meta analysis to get a better understanding of the association between sex and ICI therapy among cancer patients.
Mechanisms of sex affecting immune checkpoint inhibitor therapy
It is speculated that male patients could benefit more from ICI treatment than female patients. There are 3 potential factors for the low efficiency of ICI therapy among female patients.
The first factor is related to the sexual dimorphism of cancer biology. Even after adjusting for age at diagnosis, disease stage, smoking status, and other variables related to tumor mutation load, the tumor mutation burden (TMB) in male patients with multiple types of tumors (including melanoma and non-small cell lung cancer) was significantly higher than that in female patients (7).
The second is the sexual dimorphism of immunity. Women have a stronger immune response than men to lower the mortality of cancer. However, this also means that female tumors must escape from more effective immune surveillance mechanisms and undergo more intensive immune editing processes before metastasis can occur (8). The ability of female tumors to escape immune surveillance might reduce the immunogenicity of advanced female tumors. Moreover, compared with similar tumors in men, the immune escape mechanism is stronger in women. These factors might cause women to be more resistant to immunotherapy. In addition, women’s increased susceptibility to autoimmune diseases might make them more prone to ICI related adverse events, resulting in a higher rate of treatment discontinuation (8).
The third is the sexual dimorphism of hormones and their receptors. Estradiol, via estrogen receptorα, induces the polarization of tumor associated macrophages (TAMs) toward the immune-suppressive M2 phenotype at the expense of the anti-tumor M1 phenotype, leading to a dysfunctional cytotoxic T cell antitumor response (9). This might also damage the treatment effect of ICI in women patients.
Adverse event of ICI therapy between sexes in clinics
Unger et al. (10) explored the sex difference of immunotherapy and other therapies to evaluate the risk difference of serious adverse events between women and men among different treatment methods, including ICI therapy.
The investigators included 27 specific adverse events from 202 studies, including 13 symptomatic adverse events and 14 objective adverse events. Of all 23,296 patients, 2,319 received immunotherapy. Compared with men, all women had a 34% increased risk of serious adverse events (68.6% vs. 62.2%, P < 0.001). An increased risk of severe toxicity was observed in women in each treatment regimen, with the greatest difference in toxicity risk among immunotherapy (33.7% in women vs. 25.4% in men, P < 0.001). The association was strongest between adverse events women receiving targeted therapy or immunotherapy (OR 1.42, P < 0.001).
This study showed that among various treatment regimens, women had a higher risk of serious symptomatic adverse events, and the risk of symptomatic adverse events in women receiving immunotherapy was 66% higher than that in men. In addition, women receiving immunotherapy were more likely to have serious hematological adverse events. All these results indicated that ICI therapy differ between women and men.
Overall survival of ICI therapy between sexes in clinics
Conforti et al. (11) first explored overall survival (OS) between women and men receiving ICI by meta-analysis, which included 20 randomized controlled trials. Among them, 13 involved PD-1 inhibitors, six involved CTLA-4 inhibitors, and one involved PD-1 inhibitors combined with CTLA-4 inhibitors. There were seven trials for the treatment of melanoma, six for non-small cell lung cancer, two for head and neck cancer, one for small cell lung cancer, one for renal cell cancer, one for urethral tumor, one for gastric cancer and one for mesothelioma. eight trials were first-line treatment, and 12 were second-line or rear line treatment.
A total of 11,351 patients were included in this analysis, including 7,646 males (67%) and 3,705 females (33%). Male patients who received ICI therapy had a significantly lower risk of death than those who received control drug treatment. In female patients, ICI benefits were smaller compared with controls. Further, ICI efficacy was higher in male than in female (P = 0.0019).
However, Graham et al. (12) analyzed the data of patients with metastatic renal cell carcinoma treated with nabulizumab in the international joint database of metastatic renal cell carcinoma. A total of 294 patients received nabulizumab and 1463 patients received everolimus. The authors found that the OS outcome of navarizumab was better than that of everolimus, but sex had no effect on the efficacy of navarizumab vs. everolimus.
Wallis et al. (13) conducted a meta-analysis including 23 trials, finding that compared with other cancer therapies, the OS advantage of patients in the ICI treatment group was statistically significant. Compared with standard cancer therapy, OS benefit of ICI treatment was observed in both male and female patients, and there was no significant difference in OS advantage between male and female patients (P = 0.60).
According to these results, it seems that sex would not affect the efficiency of ICI therapy. Yet, these two studies are based on the subgroup risk ratio (HR) of published clinical trials. They are lack of analysis of individual patients while some clinical characteristics (including smoking behavior and clinicopathological subtypes) are distributed differently between men and women, which might cause bias.
Ye et al. (14) adopted an innovative method to calculate the trial specific HR ratio and applied a random effects model to calculate the pooled HR. After combining 27 clinical trials, it was found that six of the eleven trials showed the OS advantage of male patients, while the other five showed the OS advantage of female patients.
To sum up, it is still difficult to solve the debate whether sex is related to the efficacy of ICI simply by meta-analysis. Prospective clinical studies might be needed in the future to clarify the answer.
Prospective
It is important to establish an association between sex and anti-cancer immunity through further research. After all, it is easy to use hormone therapy to affect the efficacy of immunotherapy. Preliminary data suggest that blocking the androgen axis by androgen deprivation therapy (ADT) in combination with enzalutamide has the potential to reverse the resistance of tumors other than castration resistant prostate cancer to PD (L) 1 monoclonal antibody monotherapy and improve the activity of other immunotherapy regimens, such as adoptive T-cell therapy (15). It is important to evaluate the impact of controlling the androgen and estrogen axis in various conditions to understand the potential heterogeneity under different immunotherapy strategies, tumor types, patient age, and menopausal status.
Unfortunately, so far, host related factors (especially patient gender) have been largely ignored in preclinical and clinical studies of anti-tumor immunotherapy. Relatively few women were included in ICI RCTs. The low proportion of female participants could be seen in trials of different types of tumors, regardless of whether there is sex difference in tumor incidence rate. More seriously, only a very few trials used patient sex as a stratification factor in the design. Similar bias also affected preclinical studies. In cancer cell line Encyclopedia (CCLE), a cancer cell line database of Broad Institute, the proportion of male and female cell lines is unbalanced to a large extent. There are more male cell lines than female cell lines in many tumor types. Some tumor types even have no female cell lines (such as bile duct tumors and salivary gland tumors).
Moreover, most mouse experiments only used young premenopausal female mice. Although sex differences in cancer susceptibility in mice are well known, we still lack in-depth understanding of them. The results of preclinical studies including only male animals and clinical studies including only male participants do not necessarily apply to female patients. An in-depth understanding of the role played by gender in immunity and treatment will help us gain new knowledge about biological and therapeutic targets, thereby improving the prognosis of female and male cancer patients.
Funding
Start up Fund for Talent Researchers of Tsinghua University (No. 10001020507).
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Statements
Author contributions
WH, XQ, and SW conceived of the project. WH, XQ, SW, LG, and JX collected and analyzed the data. WH, XQ, and SW wrote the paper. JY provided expert guidance and suggestions. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
BagchiSYuanREnglemanEG. Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance. Annu Rev Pathol (2021) 16:223–49. doi: 10.1146/annurev-pathol-042020-042741
2
JacobsenHKleinSL. Sex differences in immunity to viral infections. Front Immunol (2021) 12:720952. doi: 10.3389/fimmu.2021.720952
3
WangLWangFSGershwinME. Human autoimmune diseases: A comprehensive update. J Intern Med (2015) 278(4):369–95. doi: 10.1111/joim.12395
4
ZhuYShaoXWangXLiuLLiangH. Sex disparities in cancer. Cancer Lett (2019) 466:35–8. doi: 10.1016/j.canlet.2019.08.017
5
DineshRKHahnBHSinghRP. PD-1, gender, and autoimmunity. Autoimmun Rev (2010) 9(8):583–7. doi: 10.1016/j.autrev.2010.04.003
6
ChakrabortyBByemerwaJShepherdJHainesCNBaldiRGongWet al. Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma. J Clin Invest. (2021) 131(23):e151347–62. doi: 10.1172/JCI151347.
7
RubinJBLagasJSBroestlLSponagelJRockwellNRheeGet al. Sex differences in cancer mechanisms. Biol Sex Differ (2020) 11(1):17. doi: 10.1186/s13293-020-00291-x
8
WangSCowleyLALiuXS. Sex differences in cancer immunotherapy efficacy, biomarkers, and therapeutic strategy. Molecules (2019) 24(18):3214–25. doi: 10.3390/molecules24183214
9
OzdemirBCDottoGP. Sex hormones and anticancer immunity. Clin Cancer Res (2019) 25(15):4603–10. doi: 10.1158/1078-0432.CCR-19-0137
10
UngerJMVaidyaRAlbainKSLeBlancMMinasianLMGotayCCet al. Sex differences in risk of severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in cancer clinical trials. J Clin Oncol (2022) 40(13):1474–86. doi: 10.1200/JCO.21.02377
11
ConfortiFPalaLBagnardiVDe PasTMartinettiMVialeGet al. Cancer immunotherapy efficacy and patients' sex: A systematic review and meta-analysis. Lancet Oncol (2018) 19(6):737–46. doi: 10.1016/S1470-2045(18)30261-4
12
BhindiBGrahamJWellsJCBakounyZDonskovFFracconAet al. Deferred cytoreductive nephrectomy in patients with newly diagnosed metastatic renal cell carcinoma. Eur Urol (2020) 78(4):615–23. doi: 10.1016/j.eururo.2020.04.038
13
WallisCJDButaneyMSatkunasivamRFreedlandSJPatelSPHamidOet al. Association of patient sex with efficacy of immune checkpoint inhibitors and overall survival in advanced cancers: A systematic review and meta-analysis. JAMA Oncol (2019) 5(4):529–36. doi: 10.1001/jamaoncol.2018.5904
14
YeYJingYLiLMillsGBDiaoLLiuHet al. Sex-associated molecular differences for cancer immunotherapy. Nat Commun (2020) 11(1):1779. doi: 10.1038/s41467-020-15679-x
15
De GiorgiUHussainMShoreNFizaziKTombalBPensonDet al. Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region. Eur J Cancer (2021) 159:237–46. doi: 10.1016/j.ejca.2021.10.015
Summary
Keywords
sex, immune checkpoint inhibitor, efficiency, cancer, adverse event
Citation
Hu W, Qian X, Wang S, Gao L, Xu J and Yan J (2022) Sex — a potential factor affecting immune checkpoint inhibitor therapy for cancers. Front. Immunol. 13:1024112. doi: 10.3389/fimmu.2022.1024112
Received
21 August 2022
Accepted
03 October 2022
Published
18 October 2022
Volume
13 - 2022
Edited by
Varun Sasidharan Nair, Helmholtz Association of German Research Centers (HZ), Germany
Reviewed by
Shixiang Wang, Sun Yat-sen University Cancer Center (SYSUCC), China
Updates
Copyright
© 2022 Hu, Qian, Wang, Gao, Xu and Yan.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xinye Qian, qianxy21@mails.tsinghua.edu.cn; Jun Yan, yanjun_1619@163.com
†These authors have contributed equally to this work
This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.