Dysfunctional BTN3A together with deregulated immune checkpoints and type I/II IFN dictate defective interplay between pDCs and gamma delta T cells in melanoma patients, which impacts clinical outcomes

Objectives. pDCs and gamma delta T cells emerge as potent immune players participating in the pathophysiology of cancers, yet still remaining enigmatic while harbouring a promising potential for clinical translations. Despite strategic and closed missions, crosstalk between pDCs and gamma delta T cells has not been deciphered yet in cancers, especially in melanoma where the long-term control of the tumor still remains a challenge. Methods. This prompted us to explore the interplay between pDCs and gamma delta T cells in the context of melanoma, investigating the reciprocal features of pDCs or gamma delta T cells, the underlying molecular mechanisms and its impact on clinical outcomes. Results. TLRL-activated pDCs from the blood and tumor infiltrate of melanoma patients displayed an impaired ability to activate, to modulate immune checkpoints and trigger the functionality of gamma delta T cells. Conversely, gamma delta T cells from the blood or tumor infiltrate of melanoma patients activated by PAg were defective in triggering pDCs' activation and modulation of immune checkpoints, and failed to elicit the functionality of pDCs. Reversion of the dysfunctional cross-talks could be achieved by specific cytokine administration and immune checkpoint targeting. Strikingly, we revealed an increased expression of BTN3A on circulating and tumor-infiltrating pDCs and gamma delta T cells from melanoma patients, but stressed out the potential impairment of this molecule. Conclusion. Our study uncovered that melanoma hijacked the bidirectional interplay between pDCs and gamma delta T cells to escape from immune control, and revealed BTN3A dysfunction. Such understanding will help harness and synergise the power of these potent immune cells to design new therapeutic approaches exploiting their antitumor potential while counteracting their skewing by tumors to improve patient outcomes.