Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 17;15(6):1815.
doi: 10.3390/cancers15061815.

Sex Differences in the Systemic and Local Immune Response of Pancreatic Cancer Patients

Azaz Ahmed  1   2 , Sophia Köhler  1 , Rosa Klotz  3 , Nathalia Giese  3 , Thilo Hackert  3 , Christoph Springfeld  1 , Dirk Jäger  1   4 , Niels Halama  1   2
Affiliations

Sex Differences in the Systemic and Local Immune Response of Pancreatic Cancer Patients

Azaz Ahmed et al. Cancers (Basel). .

Abstract

Background: Mounting evidence suggests that sex plays a critical role in various aspects of cancer such as immune responses. However, a male bias exists in human and non-human studies including immunotherapy trials. The role of sex on immune responses in pancreatic ductal adenocarcinoma (PDA) is unclear.

Methods: Here, tumor tissues (tumor and stroma separately) and corresponding blood samples from patients with PDA (n = 52) were systematically analyzed by immunohistochemistry and multiplex cytokine measurements and compared by sex.

Results: Females showed a stronger systemic immune response with higher levels of CXCL9, IL1B, IL6, IL10 and IL13. Additionally, more peripheral white blood cells were detected in females. In the microenvironment, males showed higher tumoral levels of CXCL12. No differences were detected in the stroma. Females showed a tendency towards an anti-tumoral immune cell profile. CXCL12 blockade indicated a differential microenvironmental effect by sex in an independent immunotherapy trial cohort of patients with PDA (one female, five males). The overall survival did not differ by sex in our cohort.

Conclusion: Systemic and local immune responses differ between sexes in PDA. Accordingly, sex-dependent differences need to be considered in human studies and for specific immunological interventions before clinical translation.

Keywords: CXCL12; pancreatic cancer; pancreatic ductal adenocarcinoma; sex difference; tumor immunology.

PubMed Disclaimer

Conflict of interest statement

The authors declare no potential competing interests.

Figures

Figure 1
Figure 1
Female pancreatic cancer patients show a stronger systemic immune response. (A) Scatter dot plots comparing the serum concentration of immunological parameters (as indicated) in male (n = 25) and female (n = 24) patients with PDA. (B) Scatter dot plots comparing the serum concentration of WBC and CRP in male (n = 25) and female (n = 23) patients with PDA. PDA = pancreatic ductal adenocarcinoma. WBC = white blood cells. CRP = C-reactive protein. * p ≤ 0.05, ** p ≤ 0.005.
Figure 2
Figure 2
Male patients express higher tumoral levels of CXCL12. (A) Scatter dot plots comparing the tumoral concentration of immunological parameters (as indicated) in male (n = 26) and female (n = 26) patients with PDA. The parameters were categorized into TH1- and TH2-type cytokines. (B) Scatter dot plot comparing the tumoral CXCL12 concentration in male (n = 26) and female (n = 25) patients with PDA. PDA = pancreatic ductal adenocarcinoma. * p ≤ 0.05.
Figure 3
Figure 3
Local cytokine changes upon blockade of CXCL12 (anti-CXCL12, NOX-A12) in patients with PDA of the OPERA trial. Bar plots displaying the microenvironmental cytokine changes before (biopsy on day 0) and after (biopsy on day 14) anti-CXCL12 therapy in patients with PDA (male: n = 5, female: n = 1) of the OPERA trial cohort.
Figure 4
Figure 4
Microenvironmental immune cell infiltrate in pancreatic cancer patients stratified by sex. (A) Scatter dot plots comparing the tumoral densities of different immune cell types (as indicated) in male (n = 26) and female (n = 26) patients with PDA. (B) Pie chart comparing the ratio of (typically) pro- and anti-tumoral immune cell densities (based on mean cell density) in male (n = 26) and female (n = 26) patients with PDA.
Figure 5
Figure 5
Survival of patients stratified by sex. Kaplan–Meier survival plot of male (n = 26) vs. female (n = 26) patients with PDA.
See this image and copyright information in PMC

References

    1. Dong M., Cioffi G., Wang J., Waite K.A., Ostrom Q.T., Kruchko C., Lathia J.D., Rubin J.B., Berens M.E., Connor J. Sex Differences in Cancer Incidence and Survival: A Pan-Cancer AnalysisSex Differences in Cancer Incidence and Survival. Cancer Epidemiol. Biomark. Prev. 2020;29:1389–1397. doi: 10.1158/1055-9965.EPI-20-0036. - DOI - PubMed
    1. Lopes-Ramos C.M., Quackenbush J., DeMeo D.L. Genome-wide sex and gender differences in cancer. Front. Oncol. 2020;10:597788. doi: 10.3389/fonc.2020.597788. - DOI - PMC - PubMed
    1. Rubin J.B. The spectrum of sex differences in cancer. Trends Cancer. 2022;8:303–315. doi: 10.1016/j.trecan.2022.01.013. - DOI - PMC - PubMed
    1. Rubin J.B., Lagas J.S., Broestl L., Sponagel J., Rockwell N., Rhee G., Rosen S.F., Chen S., Klein R.S., Imoukhuede P. Sex differences in cancer mechanisms. Biol. Sex Differ. 2020;11:17. doi: 10.1186/s13293-020-00291-x. - DOI - PMC - PubMed
    1. Beery A.K., Zucker I. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 2011;35:565–572. doi: 10.1016/j.neubiorev.2010.07.002. - DOI - PMC - PubMed

Grants and funding