Background & Aims

Exogenous opioids are the current standard of care for cancer pain treatment; however, they have substantial side effects and can drive immunosuppression. Immune cells are a hallmark of cancer and a major source of endogenous opioids within the tumor microenvironment (TME); B cells are the primary source of nociceptin, an understudied endogenous opioid that functions independently from other opioid systems. Tumor infiltrating B cells are critical for treatment and leveraging anti-tumor immunity for cancer pain treatment is possible. However, the involvement of the endogenous opioid system in regulating neuronal activity and subsequent anti-tumor immunity remains untested. We hypothesize that the endogenous B cell-mediated nociceptin signaling in the TME suppresses nociceptive activity and subsequently improves anti-tumor immunity.

Methods

To test this hypothesis we used clinical transcriptomic analysis of the TME from melanoma and head and neck cancer (HNC) patients to pinpoint a source of nociception (PNOC) as well as begin to understand the impact of endogenous opioid signaling in patient-reported pain, survival and anti-tumor immunity. Additionally, we used preclinical mouse models of head and neck and skin cancer to test the impact of nociceptin signaling on nociceptive behavior using von Frey and Hargreaves assays, anti-tumor immunity using flow cytometry, and tumor volume using caliper measurements. Quantitative PCR was used to verify nociceptin gene expression (Pnoc) in tumor-infiltrating B cells.

Results

In cancer patients, PNOC was identified in tertiary lymph node-forming and memory switch B cells and overall high PNOC expression was associated with increased survival. Also, in HNC patients, high B cell density was associated with less intratumoral nerve invasion (p=0.003) and correlated with less patient-reported pain (r=0.33, p=0.03). Using preclinical mouse models, we found that exogenous nociceptin given into the TME acutely attenuates nociceptive behavior in mouse models of both melanoma and oral cancer. Tongue tumor-isolated B cells had 4-fold increased Pnoc expression compared to circulating B cell from blood. In skin cancer, daily nociceptin injection reduced tumor growth and improved anti-tumor immunity. Nociceptin receptor OPRL1 antagonism heightened cancer-induced nociceptive behavior, increased tumor growth, and reduced tumor-associated immune response. Finally, high intra-tumoral Pnoc and Oprl1 levels correlated with skin and HNC patient survival.

Conclusions

Enhancing the activity of PNOC-expressing B cells or directly targeting OPRL1-expressing neurons could be a novel therapeutic strategy to manage pain in cancer patients. This approach could also stimulate anti-tumor immune responses and improve patient response to immunotherapeutic strategies to treat cancer.

References

none

Presenting Author

Nicole N. Scheff

Poster Authors

Nicole Scheff

PhD

University of Pittsburgh

Lead Author

E-mail

Andre Martel Matos

University of Pittsburgh

Lead Author

E-mail

Maryam Ahmadi

PhD.

Lead Author

E-mail

Karine Roversi

PhD

Queen's University

Lead Author

E-mail

Tuany Eichwald

Karolinska Institutet

Lead Author

E-mail

Amin Reza Nikpoor

PhD.

Lead Author

E-mail

Judith Mandl

PhD

University Hospital Heidelberg

Lead Author

E-mail

Topics

  • Mechanisms: Biological-Molecular and Cell Biology