Research Output Journal of Public Health and Medicine 4(1):19-24, 2024

ROJPHM ISSN ONLINE: 1115-9715

ISSN PRINT: 1115-6147
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Sex Disparities in Cancer Immunotherapy: A Review

Mpora Kakwanzi Evelyn

Department of Pharmacognosy Kampala International University Uganda

Email: [email protected]
ABSTRACT
Cancer immunotherapy has revolutionized cancer treatment, particularly through immune checkpoint inhibitors
(ICIs) targeting proteins like PD-1, PD-L1, and CTLA-4. While these therapies have shown significant survival
benefits across various cancers, sex-based disparities in treatment response and outcomes have emerged. This
review explores the mechanisms behind these differences, focusing on genetic, hormonal, and immune system
variations between male and female patients. Women tend to exhibit stronger immune responses due to the
presence of two X chromosomes and the immunostimulatory effects of estrogen, which enhances immune activity.
Conversely, men’s single X chromosome and the immunosuppressive effects of testosterone contribute to a less
vigorous immune response. These biological differences manifest in clinical outcomes, with men generally
experiencing better overall survival rates from ICIs, while women are more prone to immune-related adverse
events (irAEs), including autoimmune toxicities. However, in certain cases, women may demonstrate more robust
long-term survival benefits from treatments such as CTLA-4 inhibitors, despite higher toxicity risks. Beyond ICIs,
sex disparities also extend to adoptive cell therapies (ACT) and cancer vaccines, where female patients often
display stronger immune responses but face increased risks of side effects, necessitating personalized approaches to
therapy. The review also discusses emerging research on the tumor microenvironment (TME), gut microbiome,
and sex-specific pharmacokinetics and pharmacodynamics as contributing factors to these disparities.
Understanding these mechanisms is critical for improving cancer immunotherapy outcomes for both sexes. Future
research should focus on investigating the role of sex hormones, the microbiome, and developing biomarkers to
better predict responses to immunotherapy. Clinically, the findings highlight the need for tailored treatment
strategies that account for sex-specific differences, aiming for more equitable and effective cancer care.
Keywords: Cancer immunotherapy, Immune checkpoint inhibitors (ICIs), Sex-based disparities, PD-1 inhibitors,
PD-L1 inhibitors, CTLA-4 inhibitors

INTRODUCTION
Cancer immunotherapy has emerged as a groundbreaking approach to treating various types of cancer, with
immune checkpoint inhibitors (ICIs) being one of the most significant advancements in recent years [1]. ICIs,
which target proteins like PD-1, PD-L1, and CTLA-4, work by releasing the brakes on the immune system,
allowing it to recognize and attack cancer cells more effectively [2]. These therapies have revolutionized the
treatment landscape for cancers such as melanoma, non-small cell lung cancer, and renal cell carcinoma, where
they have demonstrated substantial improvements in survival rates and disease management [3]. However, the
effectiveness of immunotherapy is not uniform across all patient populations. One important factor contributing to
this variability is the patient’s sex [4]. Studies have shown that male and female patients exhibit different response
rates, experience varying side effect profiles, and have distinct survival outcomes when undergoing cancer
immunotherapy [5]. This sex-based disparity is likely influenced by a complex interplay of biological, genetic,
hormonal, and immune factors. For instance, differences in immune system regulation, hormonal levels, and
genetic expression between men and women may influence how their bodies respond to ICIs [6]. Understanding
these sex-specific differences is vital for several reasons. First, it could help clinicians tailor treatment plans more
effectively, improving outcomes for both men and women. Second, it could lead to the development of more

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(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
personalized immunotherapy strategies, where treatment is adjusted based on individual patient characteristics,
including sex [7]. Lastly, it could help reduce disparities in cancer care, ensuring that both male and female
patients receive the most effective and least harmful treatment [8]. This review aims to explore the mechanisms
behind sex-specific differences in cancer immunotherapy responses and to highlight the clinical implications of
these findings. By delving into the biological and immunological factors that contribute to these disparities, we
hope to provide insights that can enhance treatment regimens and lead to more equitable and effective cancer care
for all patients [9]. Page | 20
Biological and Immunological Differences between Sexes
Genetic and Molecular Factors: At the genetic level, men and women differ significantly due to their
chromosomal makeup—females possess two X chromosomes, while males have one X and one Y chromosome
[10]. This chromosomal distinction has a direct impact on immune function, as the X chromosome contains a high
concentration of immune-related genes, including those involved in regulating the immune system's response to
cancer [11]. For females, the presence of two X chromosomes provides genetic redundancy, meaning that even if
there are mutations or dysfunctions in one of the X-linked genes, the other chromosome can compensate, leading
to potentially more stable and robust immune responses [12].
Males, on the other hand, have only one X chromosome, making them more vulnerable to the effects of mutations
or deletions in X-linked immune-regulatory genes. This lack of genetic redundancy could explain why men are
more prone to certain infections and exhibit weaker immune responses in some scenarios, which may extend to
cancer immunotherapy. Additionally, the Y chromosome has a more limited set of genes related to immune
regulation, further contributing to the observed disparities in immune function between the sexes [13].
Hormonal Influence: Sex hormones play a critical role in shaping immune function, with estrogen and
testosterone exerting opposing effects on immune responses. Estrogen, the primary female sex hormone, enhances
immune activity by promoting the function and activation of various immune cells, including T cells,
macrophages, and dendritic cells. This hormone enhances antigen presentation, boosts the proliferation of
cytotoxic T cells, and encourages a more vigorous immune response, potentially improving the efficacy of
immunotherapies in women [14].
Conversely, testosterone, the predominant male hormone, has an immunosuppressive effect. It dampens the
immune response by reducing the activity of immune cells, leading to decreased inflammation and immune
surveillance. This immunosuppressive role of testosterone may partially explain why men tend to have weaker
responses to cancer immunotherapy. These hormonal differences highlight how sex-based variations in hormone
levels can influence immune function and may contribute to differential responses to immunotherapies in cancer
patients [15].
Immune System Differences: In general, women exhibit a more active and robust immune system compared to
men. This is reflected in their stronger responses to infections and vaccines, as well as their higher production of
pro-inflammatory cytokines [16]. The heightened immune activity in women may be advantageous in mounting
anti-tumor responses during cancer immunotherapy, leading to more effective tumor elimination. However, this
heightened immune response also comes with risks. Women are more susceptible to developing autoimmune
diseases, conditions where the immune system mistakenly attacks the body's own tissues [17]. This overactive
immune response could also contribute to women experiencing more severe immune-related adverse events
(irAEs) during cancer immunotherapy, such as inflammation of healthy organs. The increased likelihood of irAEs
in women may be a double-edged sword, providing stronger anti-tumor activity while also increasing the risk of
potentially harmful side effects [18]. Together, these biological and immunological differences between the sexes
help to explain the variability in cancer immunotherapy outcomes. Women may experience stronger immune
responses and better anti-tumor effects, but they also face a higher risk of severe side effects. On the other hand,
men may have weaker immune responses but a lower likelihood of irAEs. Understanding these differences is
crucial for developing personalized immunotherapy strategies that account for sex-based variations, ultimately
improving treatment outcomes for both men and women [19].
Clinical Evidence of Sex Disparities in Immunotherapy
Sex-based disparities in cancer immunotherapy have become evident through numerous clinical studies and trials,
particularly regarding immune checkpoint inhibitors (ICIs), adoptive cell therapies, and cancer vaccines. These
differences have significant implications for the efficacy, toxicity, and overall survival outcomes for male and
female patients [20].
Immune Checkpoint Inhibitors (ICIs): ICIs have been a major breakthrough in cancer treatment, with drugs
targeting the PD-1/PD-L1 and CTLA-4 pathways playing critical roles in enhancing the immune system's ability
to recognize and destroy cancer cells. However, the efficacy of these treatments is not the same for all patients, and
sex-based differences have been reported in several studies [21].

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
  PD-1/PD-L1 Inhibitors: These inhibitors, such as pembrolizumab and nivolumab, block the PD-1/PD-
L1 pathway, which tumors use to evade immune detection. Clinical trials in cancers such as non-small cell
lung cancer (NSCLC) and melanoma have shown that male patients often experience better overall
survival benefits compared to female patients. For example, in NSCLC, some studies suggest that men
treated with PD-1/PD-L1 inhibitors have a more prolonged survival than women.
However, while men may exhibit better survival outcomes, female patients tend to experience higher rates of
immune-related adverse events (irAEs), particularly autoimmune toxicities. Women are more prone to developing Page | 21
severe side effects such as colitis, pneumonitis, and dermatitis, which can sometimes necessitate discontinuation of
therapy [22]. This suggests that while women may experience more potent immune responses to these drugs, the
intensity of their immune system activation also puts them at greater risk for harmful side effects.
 CTLA-4 Inhibitors: CTLA-4 inhibitors, such as ipilimumab, work by blocking CTLA-4, a protein that
downregulates the immune response. Studies have shown that female patients treated with CTLA-4
inhibitors often experience more significant toxicities compared to their male counterparts. These
toxicities can include severe inflammatory responses and autoimmune disorders.
Despite the higher toxicity, female patients may also enjoy better long-term survival benefits from CTLA-4
inhibitors. For example, women with metastatic melanoma treated with ipilimumab have demonstrated improved
long-term survival rates compared to men. This suggests that although women may experience more frequent or
severe side effects, their immune systems might mount a more durable and effective anti-tumor response [23].
Adoptive Cell Therapy and Cancer Vaccines
Sex disparities are not limited to ICIs but also extend to other forms of immunotherapy, such as adoptive cell
therapies and cancer vaccines. These therapies harness the patient’s own immune cells to target and eliminate
cancer cells more effectively.
 Adoptive Cell Therapy (ACT): In ACT, T cells are extracted from a patient, engineered to enhance
their cancer-fighting abilities, and then reinfused into the body. Clinical data indicate that women
generally exhibit stronger responses to ACT than men [24]. This is likely due to women’s more robust
T-cell activity, which is influenced by genetic, hormonal, and immune system differences. For example,
female patients may generate a higher number of active T cells that can better recognize and attack tumor
cells.
On the other hand, male patients often require higher doses of T cells or combination therapies to achieve
comparable results. These combination therapies may include the use of cytokines or other immune-stimulating
agents to enhance the T-cell response in men [25]. These differences highlight the need for sex-specific
considerations in the administration and dosing of adoptive cell therapies.
 Cancer Vaccines: Cancer vaccines, which aim to stimulate the immune system to recognize and attack
cancer cells, have also shown sex-based differences in efficacy. Female patients tend to generate more
potent immune responses to cancer vaccines, likely due to their higher baseline immune activity. This
heightened response can lead to better clinical outcomes in some cases, but it may also increase the risk of
vaccine-related side effects.
In contrast, male patients often have weaker responses to cancer vaccines and may require additional
immunostimulatory interventions or combination therapies to achieve optimal efficacy [12]. These sex-based
differences in response rates further underscore the importance of personalizing immunotherapy based on patient
characteristics, including sex.
Implications for Clinical Practice
The growing body of evidence highlighting sex disparities in cancer immunotherapy has significant implications
for clinical practice. Understanding these differences can help physicians tailor treatment regimens more
effectively, potentially improving survival outcomes for both men and women [9]. For instance, clinicians might
consider closer monitoring of irAEs in female patients and the use of combination therapies or higher dosing
strategies for male patients. Personalized approaches to immunotherapy that account for sex-based biological and
immunological differences will be critical in optimizing treatment efficacy and minimizing toxicities for all
patients.
Potential Mechanisms for Sex Disparities in Immunotherapy
Tumor Microenvironment (TME): The tumor microenvironment plays a crucial role in determining the efficacy
of immunotherapy. Sex differences in the TME, such as variations in immune cell infiltration, cytokine profiles,
and the expression of immune checkpoints, can influence how male and female patients respond to treatment [10].
For instance, male patients may exhibit higher expression of immunosuppressive factors within the TME,
reducing the effectiveness of ICIs.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Microbiome Influence: Emerging research suggests that the gut microbiome plays a role in shaping the response
to immunotherapy. Differences in the gut microbiota between men and women may contribute to variations in
immune responses and treatment outcomes [9]. Certain bacterial strains have been linked to enhanced responses
to ICIs, and these strains may be more prevalent in one sex than the other.
Pharmacokinetics and Pharmacodynamics: Sex-based differences in drug metabolism and distribution also
affect immunotherapy outcomes. Women generally have a higher body fat percentage and different drug clearance
rates than men, which can alter the pharmacokinetics of immunotherapeutic agents [17]. These variations may Page | 22
require sex-specific dosing strategies to optimize treatment efficacy.
Future Directions and Research Gaps
While significant progress has been made in understanding sex disparities in cancer immunotherapy, several
research gaps remain. Future studies should focus on:
 Investigating the role of sex hormones in modulating immune responses to cancer.
 Exploring the impact of the microbiome on sex-specific immunotherapy outcomes.
 Conducting long-term studies to assess survival differences between men and women receiving various
forms of immunotherapy.
 Developing predictive biomarkers that can identify which patients are most likely to benefit from
immunotherapy based on sex-specific factors.
CONCLUSION
The review highlights the significant sex disparities in cancer immunotherapy, emphasizing the complex interplay
of biological, hormonal, and immune factors that contribute to differences in treatment outcomes between men and
women. Immune checkpoint inhibitors (ICIs), adoptive cell therapies, and cancer vaccines demonstrate varying
efficacy, toxicity, and survival rates depending on the patient's sex. Men often experience better overall survival
benefits from ICIs, while women may exhibit stronger immune responses but are at greater risk for immune-
related adverse events (irAEs). These differences are further influenced by genetic factors, hormonal variations,
and immune system activity, with women displaying more robust immune functions that can lead to both
enhanced anti-tumor activity and increased side effects.
Clinically, these findings underscore the need for personalized approaches to immunotherapy that consider sex-
based differences to optimize treatment efficacy and minimize toxicity. Future research should focus on
understanding the underlying mechanisms driving these disparities, such as the role of sex hormones, the tumor
microenvironment, and the microbiome. Additionally, long-term studies are required to develop sex-specific
treatment protocols, ensuring that both male and female patients receive the most effective and least harmful
cancer therapies. By addressing these gaps, clinicians can move toward more equitable and tailored cancer care for
all patients.
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This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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Page | 24
CITE AS: Mpora Kakwanzi Evelyn. (2024). Sex Disparities in Cancer Immunotherapy: A Review.
Research Output Journal of Public Health and Medicine 4(1):19-24.
https://doi.org/10.59298/ROJPHM/2024/411924

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.