Summary
Mononuclear phagocytes moderate tissue repair, immune activation and tolerance. In the renal tubulo-interstitium specialized dendritic cells help maintain homeostasis and protect tubuli from immune injury. Human renal cell carcinoma (RCC) is immunogenic; yet immunotherapies that target T-cell dysfunction show limited clinical efficacy suggesting additional mechanisms of immunoinhibiton. We previously described “enriched-in-renal cell carcinoma” (erc)DCs that are often found in tight contact with T cells which are dysfunctional. Here we describe that ercDCs exhibit a distinct polarization state imparted by tissue-specific signals characteristic for RCC and renal tissue homeostasis. The resulting mosaic transcript signature includes features associated with host defense activity, angiogenesis/invasion and T-cell inhibition. An ercDC-specific profile was predictive for patient survival and suggests potential therapeutic targets for improved immunotherapy.
Significance Immunotherapies, which re-invigorate T-cell activity, achieve clinical responses in subsets of patients only revealing additional layers of T-cell inhibition. Mononuclear phagocytes can be immunoinhibitory. But, they are highly plastic and repolarization may be possible if key programming molecules can be identified, potentially enabling antitumor responses in tumors refractory to checkpoint blockade. We describe a myeloid cell type with mosaic feature including tumor-promotion and immunoinhibition in human clear cell renal cell carcinoma. Observed tight contacts with T cells may translate into T-cell dysfunction. A high ercDC score in tumor tissue correlates with poor patient survival suggesting ercDCs as targets for therapeutic intervention. Targeting molecules that are identified in the ercDC profile may expand the range of patients effectively treated by immunotherapy.
Highlights Bullet points:
Renal cell carcinoma (ccRCC) harbors polarized mosaic myeloid cells (ercDCs)
ercDCs are found in contact with dysfunctional T cells in ccRCC
ercDCs express novel immunoinhibitory proteins
High ercDC z-score in ccRCC tissue correlates with poor patient survival
