Protein Kinase C Delta Regulates Mononuclear Phagocytes and Hinders Response to Immunotherapy in Cancer

Abstract

Checkpoint immunotherapy unleashes T cell antitumor potential which has revolutionized cancer treatment showing unprecedented long-term responses. However, most patients do not respond to immunotherapy which often correlates with a dysfunctional or immunosuppressive myeloid compartment. The mononuclear phagocyte system (MPS) is a sub-class of myeloid cells comprising monocytes, macrophages and dendritic cells which plays a crucial role in tissue homeostasis. However, accumulating evidence suggests that mononuclear phagocytes contribute to all phases of tumorigenesis including orchestrating inflammatory events during de novo carcinogenesis, contribution to the progression of established tumors and promotion of resistance to checkpoint blockade. Thus, targeting the MPS could be an effective strategy to enhance checkpoint blockade efficacy and promote control of tumors. Here, we found that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by mononuclear phagocytes in several human and mouse tumors. PKCδ-/- mice were more resistant to growth of various cancers compared to wild-type mice and were more responsive to anti-PD-1 immunotherapy. Furthermore, we found that tumors from PKCδ-/- mice harbor a Th-1-skewed immune landscape including increased antigen cross-presentation and T cell activation. Depletion of mononuclear phagocytes in vivo altered tumor growth in wild-type mice, but not in PKCδ-/- mice. In addition, coinjection of PKCδ-/--deficient M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to wild-type M2-like macrophages coinjected with cancer cells. Finally, intrinsic loss of PKCδ-/- functionally reprogrammed macrophages and dendritic cells by promoting their antigen presenting and cross-presenting capacity and triggered type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram mononuclear phagocytes and augment checkpoint blockade efficacy.

Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response

“…According to a pre-print research report by Chaib et al [ 303 ], PKCδ is highly expressed in mononuclear phagocytes involved in cancer growth. The absence of PKCδ in the preclinical models of knock-out mice was associated with reduced tumor development and a higher responsivity to PD-1 blockade.…”

“…Moreover, the absence of PKCδ in M2-like macrophages has been related to higher T cell activation than in the presence of wild-type M2-like macrophages, delayed tumor growth and an immune landscape skewed towards a Th1 phenotype. Lastly, the loss of PKCδ has been shown to increase Ag presenting competence in macrophages and DCs and trigger type I and type II interferon signaling, proposing PKCδ that is a reasonable target to reprogram mononuclear phagocytes and increase intra-tumor T cell migration while improving the PD-1 blockade efficacy [ 303 ].…”

“…Of note, the combined activation of PKC and CD40 has been reported to significantly reduce breast cancer growth while increasing intra-tumor CD8 + T cell activation and T RM frequency in a mouse preclinical model. This apparent discrepancy between the two studies from Chaib et al [ 303 , 305 ] prompts the requirement for more specific PKC modulators, with either an inhibitory or agonistic effect, not able to target other PKC isoforms sharing structure resemblances, which can impair the expected outcomes.…”