Immune checkpoint proteins in the local cervicovaginal cancer microenvironment

Complex interactions exist between the host, microbes and the cancer microenvironment that involve immune checkpoint proteins. This interplay between local microbiota, HPV and immune surveillance may improve our ability to diagnose cervical cancer, and predict and monitor new cancer interventions.

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Despite the availability of screening methods, such as the Pap smear and prophylactic HPV vaccination, cervical cancer continues to be a major health problem worldwide affecting approximately 570,000 women annually (1) . It is well known that persistent infection with high-risk HPV types is necessary for the development of cervical cancer, however the majority of women spontaneously clear the infection, suggesting that other factors in the local microenvironment might play a role in viral persistence, cervical dysplasia and progression to cancer.

Emerging evidence suggests that a dysbiotic vaginal microbiome can contribute to carcinogenesis in the cervicovaginal microenvironment by promoting HPV infection, but also by affecting host immune and metabolic responses (for details on the role of the microbiome in gynecologic cancer see our latest review in Nature Review Urology (2)). In our previous studies, we have demonstrated that dysbiotic vaginal microbiota is associated with elevated levels of soluble immune mediators (3), cancer biomarkers (4) as well as specific metabolites (5), which might drive progression of neoplastic disease.
Other proteins that play a role in carcinogenesis, as well as in anti-tumor responses, include immune checkpoint proteins. However, these key proteins, which are targets of novel immunotherapeutics, have been mostly investigated in the circulation, but not locally. Using a well-characterized clinical cohort and samples, we had the idea to test if these immune checkpoint proteins could be detected, let alone measured, within the local cervicovaginal microenvironment similar to other soluble immune mediators.  We found that the majority of these checkpoint proteins could be quantified in cervicovaginal lavage samples collected from patients. In fact, the proteins were measured at significantly different levels based on disease status. For example, CD40, TIM-3 and CD27 specifically and sensitively discriminated women with cervical cancer from other patient groups.
To take this work a step further we associated these differences to other features in the local microenvironment that may influence these levels, including the vaginal microbiota composition and genital inflammation. These analyses revealed a multifaceted microbiota host-immunity network and connected cervical cancer with dysbiotic microbes via LAG-3 and genital inflammation via CD40, PD-1, TIM-3 and HVEM (Fig. 1). 
Figure 1. A complex host-microbe interaction network showing associations between local immune checkpoint proteins, cervical cancer, genital inflammation and vaginal microbiome (modified from Łaniewski et al. npj Precis. Onc. 4, 22 (2020).
Collectively, our current study provides a foundation for future mechanistic studies and highlights the utility of using cervicovaginal lavages to predict responders or monitor cancer therapy for precision medicine. We are hopeful that this work will be extended by others interested in studying the local cervicovaginal microenvironment in the context of gynecologic cancer, immune monitoring and other conditions that impact women.
We would like to thank all of the patients that participated in this study and made it possible. In addition, we would like to acknowledge our clinical (Dana Chase—gynecologic oncology) and research collaborators (Haiyan Cui and Denise Roe—statistics) for their contribution to this work, as this was a highly collaborative and multidisciplinary endeavor. We are grateful for the Flinn Foundation  for supporting our research. 
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Figure 2. Drs. Łaniewski (left) and Herbst-Kralovetz (right) in the laboratory. Photo credit: Kris Hanning from University of Arizona Health Sciences.
1 Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394-424, doi:10.3322/caac.21492 (2018).
2 Łaniewski, P., Ilhan, Z. E. & Herbst-Kralovetz, M. M. The microbiome and gynaecological cancer development, prevention and therapy. Nat Rev Urol, doi:10.1038/s41585-020-0286-z (2020).
3 Łaniewski, P. et al. Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women. Sci Rep 8, 7593, doi:10.1038/s41598-018-25879-7 (2018).
4 Łaniewski, P. et al. Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis. Sci Rep 9, 7333, doi:10.1038/s41598-019-43849-5 (2019).
5 Ilhan, Z. E. et al. Deciphering the complex interplay between microbiota, HPV, inflammation and cancer through cervicovaginal metabolic profiling. EBioMedicine 44, 675-690, doi:10.1016/j.ebiom.2019.04.028 (2019).

Melissa M. Herbst-Kralovetz

Associate Professor , University of Arizona

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